CD28
T-cell-specific surface glycoprotein CD28 precursor (TP44) (CD28 antigen)
Publications[править]
Acquired immune responses mediated by CD4 T cells contribute to the initiation and progression of acute coronary syndrome (ACS). ACS patients show acquired immune system abnormalities that resemble the characteristics of autoimmune dysfunction described in the elderly. This study aimed to investigate the role of premature CD4 T cells senescence in ACS and the underlying mechanism. We compared the immunological status of 25 ACS patients, 15 young healthy individuals (C1), and 20 elderly individuals with absence of ACS (C2). The percentages of CD4 T lymphocyte subsets (including naïve, regulatory, memory and effector T cells) in peripheral blood were analyzed. In ACS patients, a significant expansion of CD4 CD28 effector T cells and a decline of CD4 CD25 CD62L Treg cells were observed. In addition, patients with ACS showed an accelerated loss of CD4 CD45RA CD62L naïve T cells and a compensatory increase in the number of CD4 CD45RO memory T cells. ACS patients demonstrated no significant difference in frequency of T cell receptor excision circles (TRECs) compared to age-matched healthy volunteers. The expression of p16 was increased while CD62L was decreased in CD4 CD28 T cells of ACS patients. Compared to healthy donors, ACS patients demonstrated the lowest telomerase activity in both CD4 CD28 and CD4 CD28 T cells. The serum levels of C-reactive protein, Cytomegalovirus IgG, [i]Helicobactor pylori[/i] IgG and [i]Chlamydia pneumonia[/i] IgG were significantly higher in ACS patients. The results suggested that the percentage of CD4 T cell subpopulations correlated with chronic infection, which contributes to immunosenescence. In conclusion, chronic infection induced senescence of premature CD4 T cells, which may be responsible for the development of ACS.
Keywords
- CD28null T cells
- CD4 T cells
- acute coronary syndrome
- immunosenescence
- infection
Immunosenescence is a process of immune dysfunction that occurs with age and includes remodeling of lymphoid organs, leading to changes in the immune function of the elderly, which is closely related to the development of infections, autoimmune diseases, and malignant tumors. T cell-output decline is an important feature of immunosenescence as well as the production of senescence-associated secretory phenotype, increased glycolysis, and reactive oxygen species. Senescent T cells exhibit abnormal phenotypes, including downregulation of CD27, CD28, and upregulation of CD57, killer cell lectin-like receptor subfamily G, Tim-3, Tight, and cytotoxic T-lymphocyte-associated protein 4, which are tightly related to malignant tumors. The role of immunosenescence in tumors is sophisticated: the many factors involved include cAMP, glucose competition, and oncogenic stress in the tumor microenvironment, which can induce the senescence of T cells, macrophages, natural killer cells, and dendritic cells. Accordingly, these senescent immune cells could also affect tumor progression. In addition, the effect of immunosenescence on the response to immune checkpoint blocking antibody therapy so far is ambiguous due to the low participation of elderly cancer patients in clinical trials. Furthermore, many other senescence-related interventions could be possible with genetic and pharmacological methods, including mTOR inhibition, interleukin-7 recombination, and NAD activation. Overall, this review aims to highlight the characteristics of immunosenescence and its impact on malignant tumors and immunotherapy, especially the future directions of tumor treatment through senescence-focused strategies.
Keywords
- Aging
- Cancer immunotherapy
- Immunosenescence
- Tumor microenvironment
- Tumor progression
Patients with systemic lupus erythematosus (SLE) have a significant increase in cardiovascular (CV) risk although they display a preserved number of circulating angiogenic CD3 CD31 CXCR4 T cells (T ), a subpopulation of T cells which promotes repair of damaged endothelium. This happens due to the concomitant expansion of a T subset with immunosenescent features, such as the loss of CD28. Therefore, the aim of this study was to elucidate the interplay between T subpopulations and endothelial cells in a group of young SLE patients without previous cardiovascular events. Twenty SLE female patients and 10 healthy controls (HCs) were recruited. Flow cytometric analysis of endothelial progenitor cells (EPCs) and T subsets were performed and serum levels of interleukin (IL)-6, -8, matrix metalloproteinase (MMP)-9 and interferon (IFN)-[i]γ[/i] were measured. Human umbilical vein endothelial cells (HUVECs) proliferation and pro-inflammatory phenotype in response to subjects' serum stimulation were also evaluated. Results showed that the percentage of T and EPC subsets was reduced in SLE patients compared with HCs, with a marked increase of senescent CD28 cells among T subset. SLE disease activity index-2000 (SLEDAI-2K) was inversed related to T cells percentage. Furthermore, IL-8 serum levels were directly correlated with the percentage of T and inversely related to the CD28 T subsets. We indirectly evaluated the role of the T subset on the endothelium upon stimulation with serum from subjects with a low percentage of T CD3 cells in HUVECs. HUVECs displayed pro-inflammatory phenotype with up-regulation of mRNA for IL-6, intercellular adhesion molecule (ICAM)-1 and endothelial leukocyte adhesion molecule (ELAM)-1. Cell proliferation rate was directly related to IL-8 serum levels and EPC percentage. In highly selected young SLE patients without previous CV events, we found that the deterioration of T compartment is an early event in disease course, preceding the development of an overt cardiovascular disease and potentially mediated by SLE-specific mechanisms. The overcome of the CD28 subset exerts detrimental role over the T phenotype, where T could exert an anti-inflammatory effect on endothelial cells and might orchestrate [i]via[/i] IL-8 the function of EPCs, ultimately modulating endothelial proliferation rate.
Keywords
- angiogenic T cells
- cardiovascular risk
- endothelial progenitor cells
- immunosenescence
- systemic lupus erythematosus
Type 2 diabetes is an important challenge given the worldwide epidemic and is the most important cause of end-stage renal disease (ESRD) in developed countries. It is known that patients with ESRD and advanced renal failure suffer from immunosenescence and premature T cell aging, but whether such changes develop in patients with less severe chronic kidney disease (CKD) is unclear. 523 adult patients with type 2 diabetes were recruited for this study. Demographic data and clinical information were obtained from medical chart review. Immunosenescence, or aging of the immune system was assessed by staining freshly-obtained peripheral blood with immunophenotyping panels and analyzing cells using multicolor flow cytometry. Consistent with previously observed in the general population, both T and monocyte immunosenescence in diabetic patients positively correlate with age. When compared to diabetic patients with preserved renal function (estimated glomerular filtration rate > 60 ml/min), patients with impaired renal function exhibit a significant decrease of total CD3 and CD4 T cells, but not CD8 T cell and monocyte numbers. Immunosenescence was observed in patients with CKD stage 3 and in patients with more severe renal failure, especially of CD8 T cells. However, immunosenescence was not associated with level of proteinuria level or glucose control. In age, sex and glucose level-adjusted regression models, stage 3 CKD patients exhibited significantly elevated percentages of CD28 , CD127 , and CD57 cells among CD8 T cells when compared to patients with preserved renal function. In contrast, no change was detected in monocyte subpopulations as renal function declined. In addition, higher body mass index (BMI) is associated with enhanced immunosenescence irrespective of CKD status. The extent of immunosenescence is not significantly associated with proteinuria or glucose control in type 2 diabetic patients. T cells, especially the CD8 subsets, exhibit aggravated characteristics of immunosenescence during renal function decline as early as stage 3 CKD. In addition, inflammation increases since stage 3 CKD and higher BMI drives the accumulation of CD8 CD57 T cells. Our study indicates that therapeutic approaches such as weight loss may be used to prevent the emergence of immunosenescence in diabetes before stage 3 CKD.
Keywords
- BMI
- CKD
- Diabetes
- Immunosenescence
- T cell
Chlamydia pneumoniae (C. pneumoniae) is a common respiratory pathogen associated with many inflammatory diseases. There are few data concerning the lymphocyte subsets in middle-aged and elderly individuals with C. pneumoniae infection. A total of 191 patients were included in this study. The study population was categorized into the middle-aged group (40-64 years old) and the elderly group (65-89 years old). Lymphocyte subsets in peripheral blood were examined with multi-colored flow cytometry. Immunological monitoring included lymphocyte subsets, C. pneumoniae IgG and IgM serology. In the middle-aged group, 69.83% individuals presented IgG positivity, which was associated with the inverted CD4/CD8 ratio. Individuals with C. pneumoniae IgG positivity also presented an increased percentage of CD8 CD28 cells and a decreased CD4/CD8 ratio when compared to weakly-positive individuals. In the elderly group, C. pneumoniae IgG positivity was associated with a significant increase in the percentage of CD3 CD56 CD45 (NKT) cells. In conclusion, altered lymphocyte homeostasis was shown in middle-aged individuals with C. pneumoniae IgG positivity. The senescent phenotypes of T cells might be associated with C. pneumoniae infection in middle-aged individuals.
Keywords
- CD4/CD8 ratio
- Chlamydia pneumoniae
- Immune profile
- Immunosenescence
- Lymphocyte subsets
Striking age-related changes occur in the human immune system, beginning in the sixth decade of life. Age is a non-modifiable, universal risk factor that results in the dysregulation of many cellular homeostatic processes. The decline in immune cell macroautophagy/autophagy and the increased generation of proinflammatory cytokines during agingfuels the development of diseases in the elderly. We reported that higher Th17 inflammation during aging was secondary to dysregulation in T cell autophagy. However, the mechanism underlying lower anti-CD3 and anti-CD28 activation-induced T cell autophagy during aging remain unknown. Our data fuel the speculation that dysregulation of the glutathione (GSH) system might cause the decline in T cell autophagy in aging, additionally provoked by reactive oxygen species signaling emanating from the mitochondria.
Keywords
- Aging
- autophagy
- glutathione
- membrane potential
- mitochondria
- oxidative stress
Optimization of antiretroviral therapy and anti-inflammatory treatments, such as statins, are among the strategies aimed at reducing metabolic disorders, inflammation and immune activation in people living with HIV (PLWH). We evaluated the potential benefit of combining both strategies. Forty-two PLWH aged ≥40 years receiving a protease inhibitor (PI)-based regimen were randomized (1:1) to switch from PI to Raltegravir (n = 20), or to remain on PI (n = 22). After 24 weeks, all patients received atorvastatin 20mg/day for 48 weeks. We analyzed plasma inflammatory as well as T-cell maturation, activation, exhaustion and senescence markers at baseline, 24 and 72 weeks. Plasma inflammatory markers remained unchanged. Furthermore, no major changes on T-cell maturation subsets, immunoactivation, exhaustion or immunosenescence markers in both CD4 and CD8 T cell compartments were observed. Only a modest decrease in the frequency of CD38 CD8 T cells and an increase in the frequency of CD28-CD57 in both CD4 and CD8 T-cell compartments were noticed in the Raltegravir-switched group. The study combined antiretroviral switch to Raltegravir and Statin-based anti-inflammatory strategies to reduce inflammation and chronic immune activation in PLWH. Although this combination was safe and well tolerated, it had minimal impact on inflammatory and immunological markers. NCT02577042.
MeSH Terms
- Adult
- Anti-HIV Agents
- Anticholesteremic Agents
- Atorvastatin
- CD4-Positive T-Lymphocytes
- CD8-Positive T-Lymphocytes
- Female
- HIV Infections
- HIV Protease Inhibitors
- Humans
- Immunosenescence
- Inflammation
- Lymphocyte Activation
- Male
- Middle Aged
- Pilot Projects
- Raltegravir Potassium
KIR NKG2A Eomes CD8 T cells, which are preferentially found with a T (CD45RA CCR7-) phenotype while having the capacity to rapidly produce IFN-γ in response to innate stimulation (IL-12 and IL-18), have been demonstrated to exist in human cord blood and the adult blood circulation. This highly responsive T-cell type was termed NK-like CD8 T cells due to their capability to act in an innate immune fashion in mice similar to NK cells. However, KIR NKG2A CD8 T cells that are Eomes- represent a small proportion of unconventional T cells that have not been described until now. We compare the distribution of the memory phenotypes and senescence-associated markers of two T-cell subsets by multicolor flow cytometry in 10 cord blood samples and 105 healthy individuals (HIs) ranging from 6 to 84 years of age. We found that the Eomes population has a higher differentiation degree than the Eomes- population. T cells in the Eomes- subset show proportionally less T phenotypes while instead preferentially displaying a more naïve and T phenotype. Furthermore, the Eomes- population was shown to linearly decrease with age, while the Eomes population exhibited more senescence-associated characteristics, such as CD57 expression and loss of CD28. Overall, the KIR NKG2A Eomes- CD8 T-cell population shares similar characteristics with the Eomes population, although with a lower degree of differentiation, lower senescence marker expression, and a proportional decrease with age. Thus, we suspect that KIR NKG2A Eomes-CD8 T cells may represent a less differentiated stage of the NK-like CD8 T-cell subset.
Keywords
- NK-like CD8 T cells
- aging
- differentiation
- memory T cell
The effect of age on the response of peripheral blood mononuclear cells (PBMCs) to immunosuppression induced by human periodontal ligament stem cells (hPDLSCs) is unclear. The identity of the cytokines most effective in inducing the PBMC immune response remains unknown. This study investigated the effects of age on immunophenotype, proliferation, activation, and cytokine secretion capacities of PBMCs following co-culture with hPDLSCs. PBMCs were collected from younger (16-19 years) and older (45-55 years) donors, then co-cultured with confirmed hPDLSCs for various lengths of time. T lymphocyte proliferation and cell surface marker expression were analyzed by flow cytometry. Cytokine expression levels were measured by quantitative polymerase chain reaction assays and enzyme-linked immunosorbent assays. CD28 expression by T lymphocytes decreased with age, indicating reduced proliferation; CD95 expression increased with age, indicating enhanced apoptosis. Moreover, hPDLSCs inhibited T lymphocyte proliferation in both age groups; this inhibition was stronger in cells from older donors than in cells from younger donors. Age reduced the secretion of interleukin-2 and interferon-γ, whereas it increased the secretion of tumor necrosis factor-β by PBMCs cultured with hPDLSCs. Aging may have a robust effect on the response of PBMCs towards hPDLSC-induced immunosuppression.
Keywords
- Periodontal ligament stem cells
- T lymphocytes
- age
- coculture
- cytokines
- immunophenotyping
- immunosenescence
- immunosuppression
- peripheral blood mononuclear cells
Aging is a natural biological process associated with cognitive decline and neuroendocrine-immune system changes; the neuroendocrine-immune system plays crucial role in brain aging and neurodegeneration, and it is essential to discern beneficial attempts to delay the aging progress based on immunological aging. In this study, we have investigated the effects of Traditional Chinese Medicine (TCM)-Liuwei Dihuang decoction (LW)-and donepezil, memantine, and melatonin on cognitive decline in aging mice. The aged SAMR1 mice received oral administration of donepezil (1mg/kg), memantine (10 mg/kg), melatonin (10 mg/kg), and LW (10 g/kg) for 3 months. A shuttle box, Morris water maze, and elevated-zero maze were performed to assess cognitive function, and flowcytometry, Luminex, and radioimmunoassay were performed to measure the lymphocyte subsets, inflammatory factors, and hormones. We observed that survival days of mice was increased with melatonin and LW, the anxiety behavior was significantly improved by memantine, melatonin, and LW treatment, active avoidance responses significantly improved by LW, donepezil, and memantine, the spatial learning ability was significantly improved by donepezil, and LW and melatonin were beneficial to the spatial memory of old mice. For immune function, LW increased CD4 and CD4 CD28 cells and reduced TNF-α, IL-1β, and G-CSF in plasma, and it also promoted the secretion of anti-inflammatory factors IL-4, IL-5, and IL-10 by regulating the active of Th2 cells in spleen. Donepezil and memantine exerted protective effects against CD4 CD28 cell decrease caused by aging and reduced the pro-inflammatory factors TNF-α, IL-1β, and G-CSF in plasma. Melatonin could reverse CD8 CD28 cell imbalances and increased B cells. For endocrine factors, LW increased TSH levels in the pituitary, and melatonin increased the GH level in blood. Our findings indicated that LW improved the cognitive decline in aging mice, and this might be associated with modulation of the active T cells and HPG axis hormones as well as increasing anti-inflammatory factors. Meanwhile, donepezil and memantine have advantages in regulating adaptive immunity, melatonin has advantages in the regulation of B cells and pituitary hormones, and LW exhibits a better effect on neuroendocrine immune function compared with the others from a holistic point of view. LW might be a potential therapeutic strategy for anti-aging-related syndromes, and it can also provide a value on medication guidance about drug combinations or treatment in clinic.
Keywords
- Liuwei Dihuang decoction
- aging
- cognition
- immune response
- inflammation
How the measurement of aging biomarkers in peripheral blood T-lymphocytes (PBTLs) is influenced by cell composition is unclear. Here, we collected peripheral blood and isolated CD3 PBTLs from 117 healthy couples between the ages of 21 and 72. Each sample was profiled for Horvath epigenetic clock (DNAm), p16INK4a expression, cytomegalovirus (CMV) seropositivity and 74 mRNA markers of PBTL subtype, differentiation, immune checkpoints, and cytokine production. Correlations between individual aging biomarkers (DNAm or p16INK4a) and PBTL mRNAs were corrected for chronological age, sex, and couple. DNAm measurements correlated with CMV seropositivity as well as PBTL mRNAs indicative of effector function (CD8A, EOMES, TBX21, GZMB), poor proliferative capacity (KLRG1, CD57), differentiation (CD45RO, CD45RA), and immune checkpoints (PDCD1, TIGIT, LAG3, CD160, CD244). In contrast, only three PBTL mRNAs, CD28, CD244, and p14ARF, showed a significant association with p16INK4a. p16INK4a expression also showed a weaker association with immunosenescent PBTL subsets than DNAm in flow cytometry analyses. These data suggest that PBTL composition has a greater influence on DNAm than p16INK4a and link accelerated epigenetic aging to immunosenescent phenotypes.
Keywords
- Aging biomarker
- CMV
- Horvath clock
- Senescence
- T cell
Aging is the most important risk factor for prostate cancer (PCa), but how age contributes to PCa is poorly understood. Aging is characterized by low-grade systemic inflammation (i.e., inflammaging) that is often attributed to the progressive activation of immune cells over time, which may play an important role in prostate carcinogenesis. Th17 response is elevated in aging humans and mice, but it remains unknown whether it is increased in prostate tissue or contributes to prostate carcinogenesis during aging. In this study, we aimed to determine the role of age-related Th17 response in PCa cell growth, migration, and invasion. C57BL/6J (B6) mouse was used as an aging animal model and the prostate histopathology during aging was analyzed. Splenic CD4 T cells were isolated from young (16-20 weeks old) and aged (96-104 weeks old) mice, and cultured in the presence of plate-bound anti-CD3/anti-CD28, with or without Th17 differentiation conditions. The cells were collected and used for subsequent flow cytometry or quantitative reverse transcription polymerase chain reaction. The supernatant was collected and used to treat PCa cell lines. The treated PCa cells were analyzed for cell viability, migration, invasion, and nuclear factor kappa B (NF-κB) signaling. Aged mice had enlarged prostate glands and increased morphological alterations, with not only increased inflammatory cell infiltration but also increased Th17 cytokines in prostate tissue, compared to young mice. Naïve CD4 T cells from aged mice differentiated increased interleukin (IL)-17-expressing cells. CD4 T cells from aged mice spleen had increased Th17 cells, Th17 cytokines and Th17/Treg ratio compared to young mice. Factors secreted from aged CD4 T cells, especially from ex vivo differentiated Th17 cells, not only promoted PCa cell viability, migration, and invasion but also activated the NF-κB signaling in PCa cells compared to young mice. These results indicate that age-related CD4 T cells, especially Th17 cells-secreted factors have the potential to contribute to prostate carcinogenesis. Our work could prompt further research using autochthonous PCa mouse models at different ages to elucidate the functional role of Th17 response in prostate carcinogenesis during aging.
MeSH Terms
- Aging
- Animals
- CD4-Positive T-Lymphocytes
- Cell Differentiation
- Cell Line, Tumor
- Cell Movement
- Humans
- Inflammation
- Male
- Mice
- Mice, Inbred C57BL
- Mice, Knockout
- Models, Animal
- NF-kappa B
- Neoplasm Invasiveness
- PC-3 Cells
- Prostatic Neoplasms
- Th17 Cells
Keywords
- CD4 T cell-secreted factors
- PCa cells
- Th17 cytokines
- aging
- inflammation
The class III NAD-dependent histone deacetylase (HDAC) sirtuin 1 (SIRT1) is an important regulator of senescence, aging, and inflammation. SIRT1de-acetylates chromatin histones, thereby silencing inflammatory gene transcription. We have reported increased steroid-resistant senescent pro-inflammatory CD28nullCD8 T cells in patients with chronic obstructive pulmonary disease (COPD). We hypothesized that SIRT1 is reduced in these cells in COPD, and that treatment with SIRT1 activators (resveratrol, curcumin) and agents preventing NAD depletion (theophylline) would upregulate SIRT1 and reduce pro-inflammatory cytokine expression in these steroid-resistant cells. Blood was collected from [i]n[/i] = 10 COPD and [i]n[/i] = 10 aged-matched controls. Expression of CD28, SIRT1, and pro-inflammatory cytokines was determined in CD8 and CD8- T and natural killer T (NKT)-like cells cultured in the presence of ±1 µM prednisolone, ±5 mg/L theophylline, ±1 µM curcumin, ±25 µM resveratrol, using flow cytometry and immunofluorescence. There was an increase in the percentage of CD28nullCD8 T and NKT-like cells in COPD patients compared with controls. Decreased SIRT1 expression was identified in CD28nullCD8 T and NKT-like cells compared with CD28 counterparts from both patients and controls (e.g. CD28null 11 ± 3% [i]versus[/i] CD28 57 ± 9%). Loss of SIRT1 was associated with increased production of IFNγ and TNFα, steroid resistance, and disease severity. SIRT1 expression was upregulated in the presence of all drugs and was associated with a decrease in steroid resistance and IFNγ and TNFα production by CD28nullCD8 T and NKT-like cells. The presence of the SIRT1 inhibitor, EX-527 negated [by 92 ± 12% (median ± SEM)] the effect of the SIRT1 activator SRT720 on the percentage of CD8 T cells producing IFNγ and TNFα. Steroid resistance in pro-inflammatory CD28nullCD8 T and NKT-like cells is associated with decreased SIRT1 expression. Treatment with prednisolone, in combination with theophylline, curcumin or resveratrol increases SIRT1 expression, restores steroid sensitivity, and inhibits pro-inflammatory cytokine production from these cells and may reduce systemic inflammation in COPD. [i]The reviews of this paper are available via the supplemental material section.[/i]
Keywords
- CD28nullCD8 T and NKT-like cells
- COPD
- IFNγ and TNFα
- SIRT1
- lymphocyte senescence
Paediatric and adolescent patients in need of allogeneic haematopoietic stem cell transplantation (HSCT) generally receive stem cells from older, unrelated or parental donors when a sibling donor is not available. Despite encouraging clinical outcomes, it has been suggested that immune reconstitution accompanied by increased replicative stress and a large difference between donor and recipient age may worsen immunosenescence in paediatric recipients. In this study, paired samples were collected at the same time from donors and recipients of haploidentical haematopoietic stem cell transplantation (HaploSCT). We then conducted flow cytometry-based phenotypic and functional analyses and telomere length (TL) measurements of 21 paired T-cell sets from parental donors and children who received T-cell-replete HaploSCT with post-transplant cyclophosphamide (PTCy). Senescent T cells, CD28 or CD57 cells, were significantly expanded in patients. Further, not only CD4 CD28 T cells, but also CD4 CD28 T cells showed reduced cytokine production capacity and impaired polyfunctionality compared with parental donors, whereas their TCR-mediated proliferation capacity was comparable. Of note, the TL in patient T cells was preserved, or even slightly longer, in senescent T cells compared with donor cells. Regression analysis showed that senescent features of CD4 and CD8 T cells in patients were influenced by donor age and the frequency of CD28 cells, respectively. Our data suggest that in paediatric HaploSCT, premature immunosenescent changes occur in T cells from parental donors, and therefore, long-term immune monitoring should be conducted.
Keywords
- CD28− T cells
- HaploSCT
- immune monitoring
- immunosenescence
- telomere length
Major depressive disorder (MDD) is associated with physiological changes commonly observed with increasing age, such as inflammation and impaired immune function. Age-related impaired adaptive immunity is characterized by the loss of naive T-cells and the reciprocal accumulation of memory T-cells together with the loss of T-cell co-stimulatory molecules. Additionally, the presence and activity of cytomegalovirus (CMV) alters the architecture of the T-cell compartment in a manner consistent with premature aging. Because CMV is also thought to reactivate with psychological stress, this study tested whether MDD influences age-related phenotypes of T-cell populations in the context of CMV infection in young and middle-aged adults. Morning blood samples from volunteers with a DSM-IV diagnosis of MDD (n = 98, mean age(SD) = 36(10) years, 74.5% female, 57.1% CMV ) and comparison controls (n = 98, mean age(SD) = 34(10) years, 68.4% female, 51.0% CMV ) were evaluated for CMV IgG antibody status and the distribution of late differentiated (CD27 CD28 ) cells within CD4 and CD8 T-cell subsets, i.e. naive (CCR7 CD45RA ), effector memory (EM, CCR7 CD45RA ), central memory (CM, CCR7 CD45RA ) and effector memory cells re-expressing CD45RA (EMRA, CCR7 CD45RA ). Mixed linear regression models controlling for age, sex, ethnicity and flow cytometry batch showed that CMV seropositivity was associated with a reduction in naive T-cells, expansion of EMRA T-cells, and a greater percent distribution of CD27 CD28 cells within CD4 and CD8 memory T-cell subsets (p's < 0.004), but there was no significant effect of MDD, nor any significant interaction between CMV and diagnosis. Unexpectedly, depressed men were less likely to be CMV and depressed women were more likely to be CMV than sex-matched controls suggesting a possible interaction between sex and MDD on CMV susceptibility, but this three-way interaction did not significantly affect the T-cell subtypes. Our findings suggest that depression in young and middle-aged adults does not prematurely advance aging of the T-cell compartment independently of CMV, but there may be significant sex-specific effects on adaptive immunity that warrant further investigation.
Keywords
- Biological aging
- Cytomegalovirus
- Depression
- Immunosenescence
- Major depressive disorder
- Sex differences
- T-cells
Patients with rheumatoid arthritis (RA) develop features of accelerated ageing, including immunosenescence. These changes include decreased thymic functionality, expansion of late-differentiated effector T cells, increased telomeric attrition, and excessive production of cytokines (senescence-associated secretory phenotype). The progression of RA has been associated with the early development of age-related co-morbidities, including osteoporosis, cardiovascular complications, and cognitive impairment. Here I review data supporting the hypothesis that immune-senescence contributes to the aggravation of both articular and extra-articular manifestations. Of note, poor cognitive functions in RA were associated with senescent CD28- T cells, inflammaging, and autoantibodies against brain antigens. The pathways of immune-to-brain communication are discussed and provide the rationale for the cognitive impairment reported in RA.
Keywords
- Ageing
- Cell senescence
- Cognitive impairment
- Immune ageing
- Rheumatoid arthritis
Cognitive impairment is common in systemic lupus erythematosus (SLE) patients with substantial adverse effects on function and quality of life. One hypothesis to understand the mechanisms of cognitive impairment in SLE is accelerated immunosenescence. The aim of this study is to observe the correlation between immunosenescence with cognitive impairment in patients with SLE. Sixty-one female SLE patient were measured for CD4 and CD8 T cell-associated senescence markers, including percentage of end-stage differentiated T cells (CD4 and CD8 T cells expressing CD57 or loss of CD28 expression), of naïve T cells (CD4 CD45RA and CD8 CD45RA ), memory T cells (CD4 CD45RO and CD8 CD45RO ), and antigen-experienced T cells (CD4 KLRG1 and CD8 KLRG1 ) which were measured using flow cytometry. One hallmark of immunosenescence called immune risk profile (IRP) was defined by an inverted ratio of CD4 and CD8. Cognitive functions were measured by Mini-Mental State Examination (MMSE) and Montréal Cognitive Assessment (MOCA) questionnaire. Thirty-six (59.1%) SLE patients who had IRP develop significantly lower attention and recall from both MMSE (P = .005 and P = .000) and MOCA (P = .017 and P = .000) examinations. Decreased visuospatial ability was also found in patients with IRP measured by MOCA (P = .046). There was a negative correlation between memory CD4 CD45RO T cells with recall and visuospatial domain (R = -0.204, P = .039 and R = -0.250, P = .033; respectively), and negative correlation between CD8 CD28 T cells with recall and attention domain (R = -0.249, P = .027 and R = -0.145, P = .048, respectively). Systemic lupus erythematosus patients develop an accelerated immunosenescence which contributes to cognitive dysfunction, especially in attention, recall, and visuospatial domains.
Keywords
- immunosenescence
- lupus-associated brain fog
- systemic lupus erythematosus
The T cell compartment undergoes characteristic changes with age, which contribute to increased incidence and severity of infections and reduced immunogenicity and efficacy of many vaccines in the older population. Production of naïve T cells is severely impaired due to a decreased output of lymphoid cells from the bone marrow and the involution of the thymus. At the same time, antigen-experienced, highly differentiated T cells accumulate resulting in a diminished T cell receptor repertoire. These cells show some similarities with senescent cells, such as shorter telomers, accumulated DNA damage and metabolic changes. Latent infection with Cytomegalovirus also impacts the T cell compartment and aggravates several of its age-associated changes. Loss of CD28 expression is one hallmark of T cells after repeated antigenic stimulation, but CD28 T cells cannot be considered truly senescent as e.g. they are still able to proliferate upon adequate stimulation. Several additional markers have been suggested in order to define a potential fully senescent T cell population, but no consensus definition has been reached so far. It has been postulated that highly differentiated senescent-like T cells are unable to eliminate other senescent cell types. Removal of senescent non-immune cells has been shown to be beneficial for the organism and a reliable definition of senescent T cells is essential for an extension of this concept to T cells.
Keywords
- Aging
- Senescence
- T cells
The multifactorial mechanisms driving negative health outcomes among risky drinkers with HIV may include immunosenescence. Immunosenescence, aging of the immune system, may be accentuated in HIV and leads to poor outcomes. The liver regulates innate immunity and adaptive immune tolerance. HIV-infected people have high prevalence of liver-related comorbidities. We hypothesize that advanced liver fibrosis/cirrhosis is associated with alterations in T-cell subsets consistent with immunosenescence. ART-naïve people with HIV with a recent history of heavy drinking were recruited into a clinical trial of zinc supplementation. Flow cytometry was used to characterize T-cell subsets. The two primary dependent variables were CD8 and CD4 T-cells expressing CD28-CD57 (senescent cell phenotype). Secondary dependent variables were CD8 and CD4 T-cells expressing CD45RO CD45RA- (memory phenotype), CD45RO-CD45RA (naïve phenotype), and the naïve phenotype to memory phenotype T-cell ratio (lower ratios associated with immunosenescence). Advanced liver fibrosis/cirrhosis was defined as FIB-4 > 3.25, APRI≥1.5, or Fibroscan measurement ≥10.5 kPa. Analyses were conducted using multiple linear regression adjusted for potential confounders. Mean age was 34 years; 25% female; 88% hepatitis C. Those with advanced liver fibrosis/cirrhosis (N = 25) had higher HIV-1 RNA and more hepatitis C. Advanced liver fibrosis/cirrhosis was not significantly associated with primary or secondary outcomes in adjusted analyses. Advanced liver fibrosis/cirrhosis was not significantly associated with these senescent T-cell phenotypes in this exploratory study of recent drinkers with HIV. Future studies should assess whether liver fibrosis among those with HIV viral suppression and more advanced, longstanding liver disease is associated with changes in these and other potentially senescent T-cell subsets.
MeSH Terms
- Adult
- Alcoholism
- CD28 Antigens
- CD4-Positive T-Lymphocytes
- CD57 Antigens
- CD8-Positive T-Lymphocytes
- Cross-Sectional Studies
- Female
- HIV Infections
- Hepatitis C
- Humans
- Immunologic Memory
- Immunosenescence
- Leukocyte Common Antigens
- Linear Models
- Liver Cirrhosis, Alcoholic
- Male
- Phenotype
- Randomized Controlled Trials as Topic
- Russia
- Zinc
Keywords
- Alcohol
- HIV
- Immune senescence
- Liver fibrosis
- Russia
To evaluate age-related changes in T cells and stem cell-related genes in mice and the changes in T cells and stem cell-related genes after allogenic bone marrow mesenchymal stem cell (BMSC) transplantation, BALB/c mice were divided into young (2 months, [i]n[/i] = 5) and old (20 months, [i]n[/i] = 5) groups and 1 × 10 BMSCs from 3-week-old C57BL/6J mice were injected into the old mice ([i]n[/i] = 5). T lymphocytes including CD3 , CD8 , CD8 CD28 , and CD8 CD44 CD62L Sca-1 stem cell-like memory T cells from spleens were analyzed by flow cytometry. mRNA transcriptions of the tumor suppressor [i]p16 [/i] and the senescence inhibiting [i]AUF 1[/i] and stem cell-related [i]ADAM12[/i], [i]GIL3[/i], [i]c-MYC[/i], [i]NANOG[/i], [i]Wnt[/i], [i]HOX11[/i], [i]Sox2[/i], [i]Oct3/4[/i], and [i]KLF4[/i] genes were analyzed by quantitative reverse transcription-polymerase chain reaction for comparison between young and old mice and old mice after BMSC application. Stem cell-related genes were reduced transcribed in old mice, an action that could be partly or completely reversed for some genes by BMSC injections. The proportion of CD8 CD28 T cells in the spleens of old mice was significantly reduced ([i]p[/i] < 0.01), indicating advanced proliferative T cell senescence. The CD8 CD44 CD62L cell fraction was significantly reduced and that of CD8 CD44 CD62L Sca-1 increased in splenic CD8 cells of old mice, both actions of which were reversed by BMSC injections. [i]p16 [/i] transcription was enhanced and [i]AUF1[/i] transcription was reduced in old mice, the latter effect partly reversed by BMSC injections. BMSC injections led to recovery of stem cell-related gene activation or BMSC stem cell-related gene expression tolerance in spleens of old mice.
Keywords
- aging
- cellular senescence
- memory T cells
- stem cell
Antigen-experienced immune cells migrate back to the bone marrow (BM), where they are maintained in BM survival niches for an extended period. The composition of T cell subpopulations in the BM changes with age, leading to an accumulation of highly differentiated T cells and a loss of naïve T cells. While innate immune cells are also affected by age, little is known about interactions between different adaptive immune cell populations maintained in the BM. In this study, the phenotype and function of innate and adaptive immune cells isolated from human BM and peripheral blood (PB) was analysed in detail using flow cytometry, to determine if the accumulation of highly differentiated T and B cells, supported by the BM niches, limits the maintenance of other immune cells, or affects their functions such as providing protective antibody concentrations. Total T cells increase in the BM with age, as do highly differentiated CD8 T cells which no longer express the co-stimulatory molecule CD28, while natural killer T (NKT) cells, monocytes, B cells, and naïve CD8 T cells all decrease in the BM with age. A negative correlation of total T cells with B cells was observed in the BM. The percentage of B cells in the BM negatively correlated with highly differentiated CD8 CD28 T cells, replicative-senescent CD8 CD57 T cells, as well as the CD8 CD28 CD57 population. Similar correlations were seen between B cells and the frequency of highly differentiated T cells producing pro-inflammatory molecules in the BM. Interestingly, plasma concentrations of diphtheria-specific antibodies negatively correlated with highly differentiated CD8 CD57 T cells as well as with exhausted central memory CD8 and CD4 T cells in the BM. A negative impact on diphtheria-specific antibodies was also observed for CD8 T cells expressing senescence associated genes such as the cell cycle regulator p21 (CDKN1A), KLRG-1, and elevated levels of reactive oxygen species (ROS). Our data suggest that the accumulation and maintenance of highly differentiated, senescent, and exhausted T cells in the BM, particularly in old age, may interfere with the survival of other cell populations resident in the BM such as monocytes and B cells, leading to reduced peripheral diphtheria antibody concentrations as a result. These findings further highlight the importance of the BM in the long-term maintenance of immunological memory.
Keywords
- Aging
- Antibodies
- B cells
- Bone marrow
- Exhaustion
- Immunosenescence
- Inflammation
- Pro-inflammatory
- Senescence
Autologous stem cell transplant (ASCT) is the standard of care for patients with multiple myeloma (MM). The clinical significance of peripheral blood T lymphocyte (PBTL) immunologic changes associated with ASCT is poorly understood. Here we evaluated T cell transcriptional messenger RNA profiles and immunophenotypes to correlate immunologic senescence, exhaustion, and anergy with clinical endpoints in a cohort of patients with MM undergoing ASCT. ASCT induced global transcriptional T cell changes and altered molecular levels of markers of T cell subtypes, T cell activation, and exhaustion. These included reduced CD4/CD8 ratio, skewing toward the Th1 subset, reduced expression of costimulatory receptors CD27 and CD28, heightened T cell activation, and increased expression of immune modulatory molecules LAG3 and PD1. Multicolor flow cytometry experiments confirmed altered circulating CD4 and CD8 subsets and skewing toward differentiated effector cells. Moreover, ASCT promoted an exhausted immunophenotype in CD3 CD4 subsets and a senescent immunophenotype in CD3 CD8 subsets. Subset-specific altered expression was also seen for surface molecules with immunomodulatory function. ASCT affected soluble levels of molecules with immunomodulatory function by increasing plasma HVEM and TIM3. High molecular LAG3 level was associated with inferior event-free survival post-ASCT (hazard ratio = 5.44; confidence interval, 1.92 to 15.46; P = .001; adjusted P [controlling for false discovery rate] = .038). Using a comprehensive evaluation of PBTLs on a molecular and phenotypic level, we have identified that ASCT induces global T cell alterations with CD4 and CD8 subset-specific changes. Moreover, LAG3 emerged as an early biomarker of adverse events post-ASCT. These findings will support the development of treatment strategies targeting immune defects in MM to augment or restore T cell responses.
Keywords
- Autologous stem cell transplant
- Exhaustion
- LAG3
- Multiple myeloma
- Senescence
MYC and RUNX oncogenes each trigger p53-mediated failsafe responses when overexpressed in vitro and collaborate with p53 deficiency in vivo. However, together they drive rapid onset lymphoma without mutational loss of p53. This phenomenon was investigated further by transcriptomic analysis of premalignant thymus from RUNX2/MYC transgenic mice. The distinctive contributions of MYC and RUNX to transcriptional control were illustrated by differential enrichment of canonical binding sites and gene ontology analyses. Pathway analysis revealed signatures of MYC, CD3, and CD28 regulation indicative of activation and proliferation, but also strong inhibition of cell death pathways. In silico analysis of discordantly expressed genes revealed Tnfsrf8/CD30, Cish, and Il13 among relevant targets for sustained proliferation and survival. Although TP53 mRNA and protein levels were upregulated, its downstream targets in growth suppression and apoptosis were largely unperturbed. Analysis of genes encoding p53 posttranslational modifiers showed significant upregulation of three genes, Smyd2, Set, and Prmt5. Overexpression of SMYD2 was validated in vivo but the functional analysis was constrained by in vitro loss of p53 in RUNX2/MYC lymphoma cell lines. However, an early role is suggested by the ability of SMYD2 to block senescence-like growth arrest induced by RUNX overexpression in primary fibroblasts.
MeSH Terms
- Animals
- Blotting, Western
- Cell Line, Tumor
- Cell Proliferation
- Cellular Senescence
- Computational Biology
- Core Binding Factor Alpha 1 Subunit
- Histone-Lysine N-Methyltransferase
- Lymphoma
- Mice
- Mice, Transgenic
- Principal Component Analysis
- Proto-Oncogene Proteins c-myc
- Receptors, Antigen, T-Cell
- Signal Transduction
- Thymus Gland
- Tumor Suppressor Protein p53
Keywords
- MYC
- RUNX
- SMYD2
- lymphoma
- p53
- senescence
Functional, tumor-specific CD8 cytotoxic T lymphocytes drive the adaptive immune response to cancer. Thus, induction of their activity is the ultimate aim of all immunotherapies. Success of anti-tumor immunotherapy is precluded by marked immunosuppression in the tumor microenvironment (TME) leading to CD8 effector T cell dysfunction. Among the many facets of CD8 T cell dysfunction that have been recognized-tolerance, anergy, exhaustion, and senescence-CD8 T cell senescence is incompletely understood. Naïve CD8 T cells require three essential signals for activation, differentiation, and survival through T-cell receptor, costimulatory receptors, and cytokine receptors. Downregulation of costimulatory molecule CD28 is a hallmark of senescent T cells and increased CD8 CD28 senescent populations with heterogeneous roles have been observed in multiple solid and hematogenous tumors. T cell senescence can be induced by several factors including aging, telomere damage, tumor-associated stress, and regulatory T (Treg) cells. Tumor-induced T cell senescence is yet another mechanism that enables tumor cell resistance to immunotherapy. In this paper, we provide a comprehensive overview of CD8 CD28 senescent T cell population, their origin, their function in immunology and pathologic conditions, including TME and their implication for immunotherapy. Further characterization and investigation into this subset of CD8 T cells could improve the efficacy of future anti-tumor immunotherapy.
MeSH Terms
- Animals
- CD28 Antigens
- CD8-Positive T-Lymphocytes
- Humans
- Immunosenescence
- Immunotherapy
- Neoplasms
Keywords
- CD8 CD28− T cells
- cancer
- cancer immunology
- glioblastoma
- immunotherapy
- malignant glioma
With advancing age, many organs exhibit functional deterioration. The age-associated accumulation of senescent cells is believed to represent one factor contributing to this phenomenon. While senescent cells are found in several different organ systems, it is not known whether they arise independently in each organ system or whether their prevalence within an individual reflects that individual's intrinsic aging process. To address this question, we studied senescence in two different organ systems in humans, namely skin and T cells in 80 middle-aged and older individuals from the Leiden Longevity Study. Epidermal p16INK4a positivity was associated with neither CD4 nor CD8 T-cell immunosenescence phenotype composites (i.e., end-stage differentiated/senescent T cells, including CD45RA CCR7 CD28 CD27 CD57 KLRG1 T cells). Dermal p16INK4a positivity was significantly associated with the CD4 , but not with the CD8 immunosenescence composite. We therefore conclude that there is limited evidence for a link between skin senescence and immunosenescence within individuals.
MeSH Terms
- Aged
- Aged, 80 and over
- CD4-Positive T-Lymphocytes
- CD8-Positive T-Lymphocytes
- Cell Differentiation
- Cellular Senescence
- Cyclin-Dependent Kinase Inhibitor p16
- Female
- Humans
- Immunosenescence
- Male
- Middle Aged
- Phenotype
- Skin
- Skin Aging
Keywords
- cellular senescence
- human
- immunosenescence
- skin aging
End-stage renal disease (ESRD) patients, including those on hemodialysis, possess a high risk for cardiovascular diseases, as the first leading cause of death among them. Traditional risk factors do not utterly elucidate this. Throughout the last two decades, CD4 CD28 T cells; an unusual subset of T lymphocytes, was detected high with excess cardiovascular (CV) mortality. We aimed to investigate the circulating CD4 CD28 T cells frequency in ESRD patients on hemodialysis and to evaluate their relationship with atherosclerotic changes. High-resolution carotid ultrasonography was done to assess the common carotid artery intima media thickness in a number of ESRD patients, accordingly patients were selected and subdivided into two groups; 30 with atherosclerosis (mean [SD] age, 51.6 [6.3] years) and 30 without (mean [SD] age, 48.9 [5.5] years). Another 30 healthy individuals (mean [SD] age, 48.5 [6.8] years) were enrolled. Analysis of CD4 CD28 T-cells frequency by flow-cytometry was performed in all studied subjects. CD4 CD28 T cell percentage was significantly higher in ESRD patients, (mean [SD], 7.3 [2.7] %) compared to healthy individuals (mean [SD], 3.0 [0.8] %), (p < 0.001). Additionally, the expansion of these unusual T lymphocytes was significantly higher in ESRD patients with atherosclerotic changes (mean [SD], 9.47 [0.75] %) compared to those without atherosclerosis (mean [SD], 5.22 [2.14] %), (p < 0.001). In conclusion circulating CD4 CD28 T lymphocyte population showed expansion in ESRD patients, and of interest in correlation to preclinical atherosclerotic changes.
MeSH Terms
- Adult
- Area Under Curve
- Atherosclerosis
- C-Reactive Protein
- CD28 Antigens
- CD4-Positive T-Lymphocytes
- Carotid Intima-Media Thickness
- Cytomegalovirus
- Cytomegalovirus Infections
- Female
- Flow Cytometry
- Humans
- Immunosenescence
- Kidney Failure, Chronic
- Lymphocytes, Null
- Male
- Middle Aged
- ROC Curve
- Renal Dialysis
Keywords
- Atherosclerosis
- CD4( )CD28(null) T cells
- Carotid intima media thickness
- ESRD
Deterioration of lung functions and degradation of elastin fibers with age are accelerated during chronic obstructive pulmonary disease (COPD). Excessive genesis of soluble elastin peptides (EP) is a key factor in the pathophysiology of COPD. We have previously demonstrated that 6-wk-old mice exhibited emphysematous structural changes associated with proinflammatory immune response after EP instillation. In this study, we investigated the consequences of aging on inflammatory, immune, and histological criteria associated with murine emphysema progression after EP exposure. Young (6 wk old) and elderly (15 mo old) C57BL/6J mice were endotracheally instilled with EP, and, at various time points after treatment, the inflammatory cell profiles from bronchoalveolar lavage fluids (BALF) and the T-lymphocyte phenotypes, at local and systemic levels, were analyzed by flow cytometry. Lungs were also prepared to allow morphological and histological analysis by confocal microscopy. Elderly mice exhibited an earlier development of pulmonary emphysema, characterized by an increase of the inflammatory and lymphocytic infiltrates, extracellular matrix breakdown, and airspace enlargement compared with young mice. This age-dependent parenchymal tissue remodeling was associated with an increase of the matrix metalloproteinase expressions and desmosine levels in BALF and/or sera of EP-treated mice. In addition, both the proportion of CD4 CD28 and CD8 CD28 T cells in the tissues of EP-treated mice and the interferon-γ levels in the EP-specific memory T-cell clones were significantly higher in elderly versus younger mice. This study demonstrates that aging accelerates emphysema development and that this effect is linked to increased EP production and their effects on inflammatory and immune response.
MeSH Terms
- Aging
- Animals
- Bronchoalveolar Lavage Fluid
- CD4-Positive T-Lymphocytes
- CD8-Positive T-Lymphocytes
- Desmosine
- Disease Models, Animal
- Elastin
- Female
- Inflammation
- Lung
- Macrophages, Alveolar
- Matrix Metalloproteinases
- Mice
- Mice, Inbred C57BL
- Neutrophils
- Proteolysis
- Pulmonary Emphysema
Keywords
- T lymphocytes
- aging
- elastin peptides
- murine emphysema
- proteases/cytokines
The aim of this study was to evaluate the DNA damage in peripheral lymphocytes and the frequencies of CD8 T cells expressing CD25, CD28 and CD45ro in aged individuals with inverted CD4:CD8 ratio. Blood samples of elderly individuals (aged >65) with normal CD4:CD8 ratio (n = 8) and inverted CD4:CD8 ratio (n = 8) were collected to identify the expression of CD25 , CD28 and CD45ro in CD8 T cells. DNA damage index was evaluated by the alkaline comet assay which was performed in lymphocytes treated with different concentrations of methyl methanesulfonate (MMS) (control non-treatment, 2 × 10 M, 4 × 10 M) for 1, 2 or 24 h. Elderly individuals with inverted CD4:CD8 ratio presented low frequency of CD8 CD28 . Moreover, low DNA damage was observed in lymphocytes of elderly with inverted CD4:CD8 ratio in different doses of MMS. Aged individuals with inverted CD4:CD8 ratio presented lower DNA damage events in peripheral lymphocytes, suggesting a resistance for cell death in T cells of individuals with immune risk profile.
MeSH Terms
- Aged
- CD4-CD8 Ratio
- Female
- Humans
- Lymphocytes
- Male
- Middle Aged
Keywords
- Aging
- DNA damage
- Immunosenescence
- Mutagenesis
- T cells
T cell lymphoproliferative disorders that arise in the skin are mainly derived from post thymic T cells most commonly of CD4 subset. Human CD4 positive T cells are dynamic exhibiting phenotypic and functional malleability. For example, with repetitive antigen exposure most commonly associated with age, CD4 positive T cells acquire a cytotoxic phenotype. The authors present four cases characterized by cutaneous infiltrates of cytotoxic CD30 negative CD4 positive T cells in the skin; three cases were forms of malignant lymphoma other than mycosis fungoides and one case was a reactive lymphomatoid photodermatosis associated with underlying collagen vascular disease. The three patients with lymphoma were adult men, two above 50 years of age and all with disseminated cutaneous disease. One of these patients whose biopsy showed a large cell morphology succumbed to the disease while one patient with localized disease responded to local radiation. In all three cases there was a nodular and diffuse pan-dermal infiltrate which was predominated by non-cerebriform atypical lymphocytes ranging from small to intermediate sized cells in two cases to a large cell dominant morphology in one case. The biopsies showed some degree of epidermotropism, and in one case it was striking. Neoplastic cells were positive for CD4, and at least one cytotoxic protein (i.e. granzyme and/or TIA). CD56, CD57 or CD30 were negative. In addition, CD28, the naïve T cell marker, was negative. Based on the few cases reported herein, one might suggest that the prognosis mirrors that seen in other forms of cutaneous T cell lymphoma with mature small cell dominant infiltrates exhibiting an indolent pattern while a CD30 negative large cell T cell lymphoma would be expected to demonstrate an aggressive clinical course.
MeSH Terms
- Aged
- CD4-Positive T-Lymphocytes
- Female
- Humans
- Immunosenescence
- Lymphoma, T-Cell, Cutaneous
- Male
- Middle Aged
- Skin Neoplasms
- T-Lymphocytes, Cytotoxic
- Young Adult
Keywords
- CD4-positive cytotoxic T cells
- Immunosenescence
- Peripheral T cell lymphoma
Inosine monophosphate dehydrogenase (IMPDH) catalyzes the conversion of IMP to xanthosine monophosphate, the rate-limiting step in [i]de novo[/i] guanosine monophosphate (GMP) synthesis. In cultured cells, IMPDH polymerizes into micron-scale filamentous structures when GMP synthesis is inhibited by depletion of purine precursors or by various drugs, including mycophenolic acid, ribavirin, and methotrexate. IMPDH filaments also spontaneously form in undifferentiated mouse embryonic stem cells and induced pluripotent stem cells, hinting they might function in various highly proliferative cell types. Therefore, we investigated IMPDH filament formation in human and murine T cells, which rely heavily on [i]de novo[/i] guanine nucleotide synthesis to rapidly proliferate in response to antigenic challenge. We discovered extensive [i]in vivo[/i] IMPDH filament formation in mature T cells, B cells, and other proliferating splenocytes of normal, adult B6 mice. Both cortical and medullary thymocytes in young and old mice also showed considerable assembly of IMPDH filaments. We then stimulated primary human peripheral blood mononuclear cells [i]ex vivo[/i] with T cell mitogens phytohemagglutinin (PHA), concanavalin A (ConA), or antibodies to CD3 and CD28 for 72 h. We detected IMPDH filaments in 40-60% of T cells after activation compared to 0-10% of unstimulated T cells. Staining of activated T cells for the proliferation marker Ki-67 also showed an association between IMPDH filament formation and proliferation. Additionally, we transferred ovalbumin-specific CD4 T cells from B6.OT-II mice into B6.Ly5a recipient mice, challenged these mice with ovalbumin, and harvested spleens 6 days later. In these spleens, we identified abundant IMPDH filaments in transferred T cells by immunofluorescence, indicating that IMPDH also polymerizes during [i]in vivo[/i] antigen-specific T cell activation. Overall, our data indicate that IMPDH filament formation is a novel aspect of T cell activation and proliferation, and that filaments might be useful morphological markers for T cell activation. The data also suggest that [i]in vivo[/i] IMPDH filament formation could be occurring in a variety of proliferating cell types throughout the body. We propose that T cell activation will be a valuable model for future experiments probing the molecular mechanisms that drive IMPDH polymerization, as well as how IMPDH filament formation affects cell function.
MeSH Terms
- Aging
- Animals
- B-Lymphocytes
- Cell Proliferation
- Female
- Humans
- IMP Dehydrogenase
- Lymphocyte Activation
- Male
- Mice
- Protein Multimerization
- T-Lymphocytes
Keywords
- IMPDH
- T cell activation
- cell proliferation
- cytoophidia
- enzyme polymerization
- lymphocytes
- purine synthesis
- rods and rings
The characteristic accumulation of late-stage differentiated CD8 T cells is enhanced by lifelong latent cytomegalovirus (CMV) persistence, which makes it challenging to screen for subclinical biomarkers of immune aging in the elderly. We systematically identified predominantly preformed, long, noncoding RNAs (lncRNAs) as integrative biomarkers of CD8 T cell aging in 14 elderly CMV carriers over 80 years of age. After sorting the CD28 CD8 T cell subset and its CD28 CD8 counterpart in five nonagenarians, we profiled the differential expression of lncRNAs and genes in CD28 CD8 T cells via array detection. We focused on 11 differentially expressed antisense lncRNAs and cross-referenced them with previously identified age-accumulated lncRNAs to create a set of candidates in CD28 CD8 T cells. We performed intracellular validation on the age-accumulated candidate lncRNAs paired with their antisense target genes using quantitative polymerase chain reaction (qPCR). Simultaneously, we sorted the CMV -specific CD8 T cell subset and its counterpart from participant cells with the HLA-A-*0201 genotype. The validated age-accumulated lncRNAs in CD28 CD8 T cells were intracellularly cross-validated in CMV CD8 T cells. Finally, we identified the immunity-related gene(s) that acted as potential target(s) to the cross-validated age-accumulated lncRNA(s), using bioinformatics techniques. The potential regulation of the final identified lncRNA-gene pair(s) was simultaneously predicted in two pathway-integrated networks. We concluded that expression of an age-accumulated lncRNA (NRON) was decreased, whereas that of its immunity-related target gene (NFAT) was increased, in both CD28 CD8 T cells and CMV CD8 T cells of elderly individuals with persistent CMV infection. The identification of NRON as a potential biomarker suggests that NRON contributes to CMV-enhanced CD28 CD8 T cell aging by modulating phosphorylation and/or IL-4-dependent NFAT signaling.
MeSH Terms
- Aged, 80 and over
- Biomarkers
- CD28 Antigens
- CD8-Positive T-Lymphocytes
- Cytomegalovirus
- Cytomegalovirus Infections
- Female
- Humans
- Immunosenescence
- Lymphocyte Activation
- Male
- NFATC Transcription Factors
- RNA, Long Noncoding
- T-Lymphocyte Subsets
Keywords
- Bioinformatics
- Biomarkers
- CMV persistence
- Immune aging
- T cell
Several studies have demonstrated T cell alteration and some features of immunosenescence in thalassemia major. Repeated alloimmunization converts naïve T-cells to memory cells and iron overload causes oxidative stress accelerating immune aging. To determine whether the alteration of T-cell cytokine is matched with early immune aging, the quantity of cytokine expressing T cells and their correlation to some immune aging markers were investigated. The proportion of IL2- and IFNγ expressing CD4 and CD8 T-cells was measured in 27 hepatitis B, C and HIV negative B-thalassemia patients and a control group aged 10-30 years, following stimulation for 6 h with streptococcus enterotoxin B and intracellular cytokine staining. This proportion then were analyzed versus the percentage of the T-cells expressing each phenotyping marker, CD27, CD28, CD57 and CCR7. CD4 and CD8 positive T cells expressing IL-2 were significantly lower in β-thalassemia major compared to matched controls, but not T cells expressing IFNγ. No significant difference was observed between splenectomized and non-splenectomized patients in cytokine expressing T cells. A negative correlation was noted between the percentage of T cells expressing IFNγ and T-cells expressing CD-27, but not other markers. Lower T cells expressing IL-2 may reveal the decline of naïve and central memory T cells and is likely to be a feature of early immune aging. Decreased antigenic stimulation and iron overload may help to prevent this phenomenon.
Keywords
- Cytokine
- Immunosenescence
- Intracellular
- T lymphocyte
- Thalassemia major
An increased risk of cardiovascular death in Cytomegalovirus (CMV)-infected individuals remains unexplained, although it might partly result from the fact that CMV infection is closely associated with the accumulation of CD28 T-cells, in particular CD28 CD4 T-cells. These cells can directly damage endothelium and precipitate cardiovascular events. However, the current paradigm holds that the accumulation of CD28 T-cells is a normal consequence of aging, whereas the link between these T-cell populations and CMV infection is explained by the increased prevalence of this infection in older people. Resolving whether CMV infection or aging triggers CD28 T-cell expansions is of critical importance because, unlike aging, CMV infection can be treated. We used multi-color flow-cytometry, antigen-specific activation assays, and HLA-typing to dissect the contributions of CMV infection and aging to the accumulation of CD28 CD4 and CD8 T-cells in CMV and CMV- individuals aged 19 to 94 years. Linear/logistic regression was used to test the effect of sex, age, CMV infection, and HLA-type on CD28 T-cell frequencies. The median frequencies of CD28 CD4 T-cells and CD28 CD8 T-cells were >12-fold (p=0.000) but only approximately 2-fold higher (p=0.000), respectively, in CMV (n=136) compared with CMV- individuals (n=106). The effect of CMV infection on these T-cell subsets was confirmed by linear regression. Unexpectedly, aging contributed only marginally to an increase in CD28 T-cell frequencies, and only in CMV individuals. Interestingly, the presence of HLA-DRB1*0301 led to an approximately 9-fold reduction of the risk of having CD28 CD4 T-cell expansions (OR=0.108, p=0.003). Over 75% of CMV-reactive CD4 T-cells were CD28 . CMV infection and HLA type are major risk factors for CD28 CD4 T-cell-associated cardiovascular pathology. Increased numbers of CD28 CD8 T-cells are also associated with CMV infection, but to a lesser extent. Aging, however, makes only a negligible contribution to the expansion of these T-cell subsets, and only in the presence of CMV infection. Our results open up new avenues for risk assessment, prevention, and treatment.
MeSH Terms
- Adult
- Aged
- Aged, 80 and over
- Aging
- CD28 Antigens
- CD4-Positive T-Lymphocytes
- Cytomegalovirus Infections
- Female
- Flow Cytometry
- Heart Failure
- Histocompatibility Testing
- Humans
- Male
- Middle Aged
- Prevalence
- Risk Factors
- Young Adult
Keywords
- CD28null CD4 T-cells
- CD28null CD8 T-cells
- Cytomegalovirus
- aging
- cardiovascular disease
- coronary complications
Recent studies suggest that the age-related remodeling of the immune system, known as immunosenescence, could impact the efficacy of immune checkpoint inhibitors in leukemia or nonsmall cell lung cancer. We investigated whether senescence markers can predict response to checkpoint inhibitor therapy in melanoma patients. The peripheral blood of patients with newly diagnosed, untreated metastatic melanoma was analyzed by flow cytometry to correlate the frequency of senescence markers with clinical response as measured by RECIST after 12 weeks of treatment with immune checkpoint inhibitors. The loss of surface markers CD27 and CD28 or the expression of Tim-3 and CD57 on T cells was associated with resistance to checkpoint inhibitor blockade, presenting these phenotypes as possible predictive biomarkers for checkpoint inhibitor therapy. Immunosenescence seems to impact on the response to checkpoint inhibitor therapy in melanoma patients. Thus, lymphocyte phenotyping for senescence markers, with the introduction of immunosenescence panels, could be predictive for checkpoint inhibitor response.
MeSH Terms
- Aged
- Aged, 80 and over
- Biomarkers, Tumor
- CD28 Antigens
- CD57 Antigens
- Female
- Flow Cytometry
- Hepatitis A Virus Cellular Receptor 2
- Humans
- Immunosenescence
- Lymphocytes
- Male
- Melanoma
- Middle Aged
- Tumor Necrosis Factor Receptor Superfamily, Member 7
Keywords
- biomarker
- immune checkpoint inhibitors
- immunosenescence
- melanoma
The objective was to assess the proportion of Th1, Th2 and Th17 phenotypes in senescent CD4 CD28 cells from patients with systemic lupus erythematosus (SLE) and its association with the pattern of joint involvement. This cross-sectional study was performed in SLE patients with erosive arthritis (rhupus) or nondeforming, nonerosive arthritis. Total CD4 CD28 cells as well as the proportion of these cells expressing T-bet, GATA3 or RORγt were analyzed by color-flow cytometry. Serum osteopontin levels were measured by ELISA. Eighteen SLE patients (nine with rhupus and nine with nonerosive arthritis) were studied. The percentage of CD4 CD28 /CD4 cells (17.7%, 10.3-25.0% versus 9.4%, 8.1-22.4%; P = 0.386) as well as the osteopontin levels (5800, 5,134-5995 pg/ml versus 5578, 5171-5717 pg/ml; P > 0.05) were similar in both groups. A higher percentage of CD4 CD28 T-bet cells (42.8%, 33.5-53.4% versus 30.0%, 23.3-34.2%) but a lower percentage of CD4 CD28 GATA3 cells (3.1%, 1.7-5.6% versus 6.2%, 2.6-18.4%) was observed in patients with rhupus than in their counterparts ( P = 0.016). The frequency of CD4 CD28 RORγt cells was similar between groups. In patients with rhupus, senescent CD4 CD28 cells are preferentially polarized to a Th1 phenotype, whereas this is partial towards Th2 in lupus patients with a nonerosive arthritis pattern.
MeSH Terms
- Adult
- Arthritis
- Cross-Sectional Studies
- Female
- Flow Cytometry
- Humans
- Lupus Erythematosus, Systemic
- Male
- Mexico
- Middle Aged
- Phenotype
- T-Lymphocytes, Helper-Inducer
Keywords
- CD4 CD28null cells
- Systemic lupus erythematosus
- arthritis
- osteopontin
- rhupus
- senescence
Adults exposed to childhood maltreatment have increased stress reactivity. This profile is associated with dysregulation of the immune system, including enhanced inflammatory reactions and accelerated senescence. Subjects exposed to ear stress have increased risk for several age-related diseases, including cardiovascular disease, type II diabetes, and cancer. Although previous studies have reported immune changes in advanced cancer, very little information is available regarding early stage breast cancer. Here, 29 patients with breast cancer were recruited: 15 with history of childhood maltreatment (CM ) and 14 without history (CM-). Twenty-seven healthy women without CM were selected as the control group. Peripheral blood was collected and lymphocyte subsets phenotyped by multi-color flow cytometry (B cells, CD4 T, CD8 T, natural killer cells, activated T cells, regulatory T cells, and senescence-associated T cells). Because human cytomegalovirus (CMV) was associated with signatures of early senescence, the CMV serology was determined by ELISA. None of the subjects had IgM reactivity to CMV, excluding acute viral infection. There was a higher proportion of patients with increased CMV IgG levels in the CM group as compared to CM- or controls. Different stages of T-cell differentiation can be determined based on the cell-surface expression of the costimulatory molecules CD27 and CD28: ear (CD27 CD28 ), intermediate-differentiated (CD27-CD28 ), and late-differentiated or senescent T cells (CD27-CD28-). After adjusting for age and education, ear T cells (CD27 CD28 ) were found reduced in CM and CM- patients ([i]p[/i] < 0.0001). In contrast, intermediate-differentiated T cells (CD27-CD28 ; [i]p[/i] < 0.0001), senescent T cells (CD27-CD28-; [i]p[/i] < 0.0001), and exhausted T cells (CD8 CD27-CD28-PD1 ; [i]p[/i] < 0.0001) were found expanded in both CM and CM- groups. Our data suggest that features of immunosenescence are associated with newly diagnosed breast cancer, regardless of the CM history.
Keywords
- T lymphocytes
- breast cancer
- childhood maltreatment
- cytomegalovirus
- immunosenescence
This study aimed to evaluate whether ICU patients who developed persistent critical illness displayed an immune profile similar to an aged immune phenotype and any associations with patient outcomes. Twenty two critically ill ICU patients (27-76 years, 15 males), at day 5 of mechanical ventilation, and 22 healthy age-matched controls (27-77 years, 13 males) were recruited. Frequency and phenotype of innate and adaptive immune cells and telomere length in peripheral blood mononuclear cells (PBMCs) were measured. An elevated granulocyte count (p < 0.0001), increased numbers of immature granulocytes (p < 0.0001), increased CD16 monocytes (p = 0.003) and CD14 HLADR monocytes (p = 0.004) and lower NK cell numbers (p = 0.007) were observed in ICU patients compared to controls. Critically ill patients also had lower numbers of total T lymphocytes (p = 0.03), naïve CD4 T cells (p = 0.003) and PTK7 recent thymic emigrants (p = 0.002), and increased senescent CD28 CD57 CD4 T cells (p = 0.02), but there was no difference in PBMC telomere length. Regulatory immune cell frequency was affected with reduced circulating CD19 CD24 CD38 regulatory B cells (p = 0.02). However, only a raised neutrophil:lymphocyte ratio and reduced frequency of CD14 HLADR monocytes were associated with poor outcomes. We conclude that persistent critical illness results in changes to immune cell phenotype only some of which are similar to that seen in physiological ageing of the immune system.
MeSH Terms
- Adult
- Aged
- Aging
- Critical Illness
- Female
- Healthy Volunteers
- Humans
- Immunity, Cellular
- Intensive Care Units
- Leukocyte Count
- Leukocytes, Mononuclear
- Male
- Middle Aged
- Phenotype
- Telomere Homeostasis
T-cell immunosenescence, a hallmark of an aging immune system, is potentially linked to the risk of developing cancer and other aging-related diseases. Chronic infection by cytomegalovirus (CMV) has been widely studied as a risk factor for T-cell immunosenescence, but the role of persistent chemicals has never been examined. As a typical example of persistent chemicals, we evaluated whether organochlorine pesticides (OCPs) are related to T-cell immunosenescence in the general population. Serum concentrations of β-hexachlorocyclohexane, [i]p,p[/i]'-DDT, [i]p,p[/i]'-DDE, and trans-nonachlor were measured in 95 Korean adults ages 30 to 64 years. T-cell immunosenescence was assessed by the frequencies of CD8 CD57 , CD8 CD28 , CD4 CD57 , and CD4 CD28 T lymphocytes in 20 mL of fresh peripheral blood. The senescence of CD8 T lymphocytes was the most consistently associated with OCPs. For quartiles of measurements of OCPs, adjusted mean percentages of CD8 CD57 and CD8 CD28 T lymphocytes in the CD8 T lymphocyte population were 23.9, 27.6, 31.0, and 38.7 ([i]P[/i] < 0.01) and 25.6, 27.3, 28.0, and 35.5 ([i]P[/i] = 0.02), respectively. When we compared the strength of the associations among OCPs, CMV IgG titer, and age, OCPs showed the strongest association with markers of immunosenescence. Importantly, the association between OCPs and immunosenescence markers was more prominent among participants without known risk factors, such as a young age or low CMV immunoglobulin G titer. Chronic exposure to low-dose OCPs may be a new risk factor for T-cell immunosenescence. T-cell immunosenescence may be one possible mechanism linking low-dose OCPs and many chronic diseases. [i]Cancer Epidemiol Biomarkers Prev; 27(10); 1159-67. ©2018 AACR[/i].
MeSH Terms
- Adult
- Female
- Follow-Up Studies
- Hexachlorocyclohexane
- Humans
- Immunosenescence
- Male
- Middle Aged
- Pesticides
- Prognosis
- Risk Factors
- T-Lymphocytes
Loss of CD28 is a characteristic feature of T cell aging, but the underlying mechanisms of this loss are elusive. As differential expression of microRNAs (miRNAs) has been described between CD28 and CD28- T cells, we hypothesized that altered miRNA expression contributes to the age-associated downregulation of CD28. To avoid the confounding effects of age-associated changes in the proportions of T cells at various differentiation stages [i]in vivo[/i], an experimental model system was used to study changes over time in the expression of miRNA associated with the loss of CD28 expression in monoclonal T cell populations at a lower or higher number of population doublings (PDs). This approach allows identification of age-associated miRNA expression changes in a longitudinal model. Results were validated in [i]ex vivo[/i] samples. The cumulative number of PDs but not the age of the donor of the T cell clone was correlated with decreased expression of CD28. Principal component analysis of 252 expressed miRNAs showed clustering based on low and high PDs, irrespective of the age of the clone donor. Increased expression of miR-9-5p and miR-34a-5p was seen in clones at higher PDs, and miR-9-5p expression inversely correlated with CD28 expression in [i]ex vivo[/i] sorted T-cells from healthy subjects. We then examined the involvement of miR-9-5p, miR-34a-5p, and the members of the miR-23a~24-2 cluster, in which all are predicted to bind to the 3'UTR of CD28, in the IL-15-induced loss of CD28 in T cells. Culture of fresh naive CD28 T cells in the presence of IL-15 resulted in a gradual loss of CD28 expression, while the expression of miR-9-5p, miR-34a-5p, and members of the miR-23a~24-2 cluster increased. Binding of miR-9-5p, miR-34a-5p, miR-24-3p, and miR-27- 3p to the 3'UTR of CD28 was studied using luciferase reporter constructs. Functional binding to the 3'UTR was shown for miR-24-3p and miR-27a-3p. Our results indicate involvement of defined miRNAs in T cells in relation to specific characteristics of T cell aging, i.e., PD and CD28 expression.
Keywords
- CD28
- IL-15
- T cell aging
- miR-23a~24-2
- miR-9
- miRNA
- senescence
Aging is associated with elevated cardiovascular disease risk. As a result of aging, endothelial dysfunction develops, partly due to a reduction in vascular regenerative ability. CD31 T cells (angiogenic T cells; T ) possess highly angiogenic capabilities; however, these cells are significantly reduced in older populations. In addition, older populations possess significantly higher senescent and highly differentiated T-cell levels in circulation, and these are reported to be highly exercise responsive. We investigated whether older adults display greater levels of circulating senescent (CD28 ) T cells and whether these cells were more exercise responsive than CD28 T cells. Young (18-25 years; n = 9) and older (60-75 years; n = 10) healthy men undertook a 30-min cycling bout at 70% V˙O peak, with circulating T cells (CD3 CD31 CD28 ; including CD4 and CD8 subsets) measured preexercise, postexercise, and 1 h post exercise by flow cytometry. Older adults displayed reduced basal levels of T cells (mean ± SEM: 410 ± 81 vs. 784 ± 118 cells·μL, P = 0.017), despite a greater proportion of these cells being CD28 (26.26 ± 5.08 vs. 13.36 ± 2.62%, P = 0.044). Exercise significantly increased the circulating number of T cells in both young and older men. However, in older men alone, exercise preferentially mobilized CD28 CD8 T cells compared with CD28 T cells (time × phenotype interaction: P = 0.022; Δ74 ± 29 vs. Δ27 ± 15 cells·μL, P = 0.059), with no such difference observed between these phenotypes in the young population. In conclusion, this is the first study to demonstrate that despite observing lower circulating numbers of T cells, older adults display greater levels of senescent T cells in comparison with younger individuals, and these cells are more exercise responsive than CD28 T cells. Lower number of circulating T and greater levels of senescent-associated CD28 T may contribute to greater CVD risk with advancing age.
MeSH Terms
- Adolescent
- Adult
- Aged
- Aging
- CD28 Antigens
- Cellular Senescence
- Exercise
- Flow Cytometry
- Humans
- Immunophenotyping
- Lymphocyte Count
- Male
- Middle Aged
- Neovascularization, Physiologic
- Oxygen Consumption
- T-Lymphocyte Subsets
- Young Adult
Keywords
- Age
- Angiogenic T cells
- CD28
- Exercise
While dogs are increasingly being utilized as large-animal models of disease, important features of age-related immunosenescence in the dog have yet to be evaluated due to the lack of defined naïve vs. memory T lymphocyte phenotypes. We therefore performed multi-color flow cytometry on peripheral blood mononuclear cells from young and aged beagles, and determined the differential cytokine production by proposed memory subsets. CD4 and CD8 T lymphocytes in aged dogs displayed increased cytokine production, and decreased proliferative capacity. Antibodies targeting CD45RA and CD62L, but less so CD28 or CD44, defined canine cells that consistently exhibited properties of naïve-, central memory-, effector memory-, and terminal effector-like CD4 and CD8 T lymphocyte subsets. Older dogs demonstrated decreased frequencies of naïve-like CD4 and CD8 T lymphocytes, and an increased frequency of terminal effector-like CD8 T lymphocytes. Overall findings revealed that aged dogs displayed features of immunosenescence similar to those reported in other species.
MeSH Terms
- Aging
- Animals
- CD4-Positive T-Lymphocytes
- CD8-Positive T-Lymphocytes
- Cells, Cultured
- Cytokines
- Dogs
- Flow Cytometry
- Immunologic Memory
- L-Selectin
- Leukocyte Common Antigens
- Leukocytes, Mononuclear
- Lymphocyte Subsets
- Male
Keywords
- CD45RA
- Canine
- Immunosenescence
- Inflammaging
- T lymphocyte
A wealth of evidence implicates both central and peripheral immune changes as contributing to the pathogenesis of Parkinson's disease (PD). It is critical to better understand this aspect of PD given that it is a tractable target for disease-modifying therapy. Age-related changes are known to occur in the immune system (immunosenescence) and might be of particular relevance in PD given that its prevalence rises with increasing age. We therefore sought to investigate this with respect to T cell replicative senescence, a key immune component of human ageing. Peripheral blood mononuclear cells were extracted from blood samples from 41 patients with mild PD (Hoehn and Yahr stages 1-2, mean (SD) disease duration 4.3 (1.2) years) and 41 age- and gender-matched controls. Immunophenotyping was performed with flow cytometry using markers of T lymphocyte activation and senescence (CD3, CD4, CD8, HLA-DR, CD38, CD28, CCR7, CD45RA, CD57, CD31). Cytomegalovirus (CMV) serology was measured given its proposed relevance in driving T cell senescence. Markers of replicative senescence in the CD8 population were strikingly reduced in PD cases versus controls (reduced CD57 expression (p = 0.005), reduced percentage of 'late differentiated' CD57 CD28 cells (p = 0.007) and 'TEMRA' cells (p = 0.042)), whilst expression of activation markers (CD28) was increased (p = 0.005). This was not driven by differences in CMV seropositivity. No significant changes were observed in the CD4 population. This study demonstrates for the first time that the peripheral immune profile in PD is distinctly atypical for an older population, with a lack of the CD8 T cell replicative senescence which characterises normal ageing. This suggests that 'abnormal' immune ageing may contribute to the development of PD, and markers of T cell senescence warrant further investigation as potential biomarkers in this condition.
MeSH Terms
- Aged
- Aging
- Antigens, CD
- Case-Control Studies
- Cellular Senescence
- Cytomegalovirus
- Female
- Flow Cytometry
- Humans
- Immunoglobulin G
- Immunophenotyping
- Immunosenescence
- Leukocytes, Mononuclear
- Male
- Middle Aged
- Parkinson Disease
- Serology
- T-Lymphocytes
Keywords
- Immune markers
- Immunosenescence
- Parkinson’s disease
- T cells
Premature T-cell immunosenescence with CD57 CD8 T-cell accumulation has been linked to immunodeficiency and autoimmunity in primary immunodeficiencies including activated PI3 kinase delta syndrome (APDS). To address whether CD57 marks the typical senescent T-cell population seen in adult individuals or identifies a distinct population in APDS, we compared CD57 CD8 T cells from mostly pediatric APDS patients to those of healthy adults with similarly prominent senescent T cells. CD57 CD8 T cells from APDS patients were less differentiated with more CD27 CD28 effector memory T cells showing increased PD1 and Eomesodermin expression. In addition, transition of naïve to CD57 CD8 T cells was not associated with the characteristic telomere shortening. Nevertheless, they showed the increased interferon-gamma secretion, enhanced degranulation and reduced in vitro proliferation typical of senescent CD57 CD8 T cells. Thus, hyperactive PI3 kinase signaling favors premature accumulation of a CD57 CD8 T-cell population, which shows most functional features of typical senescent T cells, but is different in terms of differentiation and relative telomere shortening. Initial observations indicate that this specific differentiation state may offer the opportunity to revert premature T-cell immunosenescence and its potential contribution to inflammation and immunodeficiency in APDS.
MeSH Terms
- CD57 Antigens
- Cell Differentiation
- Cellular Senescence
- Class I Phosphatidylinositol 3-Kinases
- Cytokines
- Humans
- Immunologic Deficiency Syndromes
- Immunophenotyping
- Lymphocyte Count
- Phosphatidylinositol 3-Kinases
- Primary Immunodeficiency Diseases
- Sirolimus
- T-Lymphocyte Subsets
- Telomere Shortening
Keywords
- Activated PI3Kdelta syndrome
- CD57
- T-cell differentiation
- T-cell senescence
- immunodeficiency
- telomeres
Cytomegalovirus (CMV) infection has recently been associated with a lower multiple sclerosis (MS) susceptibility, although it remains controversial whether it has a protective role or is merely an epiphenomenon related to westernization and early-life viral infections. We aimed to evaluate whether CMV serostatus may differ in patients with early MS as compared with patients with non-early MS, analyzing the putative association of this virus with MS clinical course and humoral immune responses against other herpesviruses. Multicentric analysis was undertaken of 310 patients with MS (early MS, disease duration ≤5 years, n = 127) and controls (n = 155), evaluating specific humoral responses to CMV, Epstein-Barr virus and human herpesvirus-6, as well as T-cell and natural killer (NK)-cell immunophenotypes. Cytomegalovirus seroprevalence in early MS was lower than in non-early MS or controls (P < 0.01), being independently associated with disease duration (odds ratio, 1.04; 95% confidence interval, 1.01-1.08, P < 0.05). CMV patients with MS displayed increased proportions of differentiated T-cells (CD27-CD28-, CD57 , LILRB1 ) and NKG2C NK-cells, which were associated with a lower disability in early MS (P < 0.05). CMV patients with early MS had an age-related decline in serum anti-EBNA-1 antibodies (P < 0.01), but no CMV-related differences in anti-human herpesvirus-6 humoral responses. Low CMV seroprevalence was observed in patients with early MS. Modification of MS risk attributed to CMV might be related to the induction of differentiated T-cell and NK-cell subsets and/or modulation of Epstein-Barr virus-specific immune responses at early stages of the disease.
MeSH Terms
- Adult
- Antibodies, Viral
- Cytomegalovirus
- Cytomegalovirus Infections
- Female
- Humans
- Hygiene Hypothesis
- Male
- Middle Aged
- Multiple Sclerosis
- Seroepidemiologic Studies
- Young Adult
Keywords
- Epstein-Barr virus
- cytomegalovirus
- herpesvirus
- hygiene hypothesis
- immunosenescence
- multiple sclerosis
- natural killer cells
T-cells are critical players in the pathogenesis of osteoporosis in patients with rheumatoid arthritis (RA). Premature senescence of lymphocytes including the accumulation of senescent CD4 T-cells is a hallmark feature of RA. Whether T-cell senescence is associated with bone loss in RA patients is elusive so far. This includes a prospective study of consecutive patients with RA ([i]n[/i] = 107), patients with primary osteopenia/-porosis ([i]n[/i] = 75), and healthy individuals ([i]n[/i] = 38). Bone mineral density (BMD) was determined by dual-energy X-ray absorptiometry scan. Flow cytometry, magnetic-associated cell sorting, and cell culture experiments were performed to analyze the pro-osteoclastic phenotype and the function of senescent CD4 CD28 T-cells. Patients with osteopenia/-porosis yielded a higher prevalence of senescent CD4 CD28 T-cells than individuals with normal BMD, in the RA, as well as in the non-RA cohort. Receptor activator of nuclear factor kappa-B ligand (RANKL) was expressed at higher levels on CD4 CD28 T-cells as compared to CD28 T-cells. Stimulation with interleukin-15 led to an up-regulation of RANKL expression, particularly on CD28 T-cells. CD4 CD28 T-cells induced osteoclastogenesis more efficiently than CD28 T-cells. Our data indicate that senescent T-cells promote osteoclastogenesis more efficiently than conventional CD28 T-cells, which might contribute to the pathogenesis of systemic bone loss in RA and primary osteoporosis.
MeSH Terms
- Absorptiometry, Photon
- Aged
- Arthritis, Rheumatoid
- Biomarkers
- Bone Density
- Bone Resorption
- CD4-Positive T-Lymphocytes
- Cell Differentiation
- Cellular Senescence
- Cytokines
- Female
- Humans
- Immunophenotyping
- Male
- Middle Aged
- Osteoclasts
- RANK Ligand
- T-Lymphocytes
Keywords
- IL-15
- T-lymphocyte
- aging
- osteoporosis
- rheumatoid arthritis
Aging is associated with immune dysfunction, especially T-cell defects, which result in increased susceptibility to various diseases. Previous studies showed that T cells from aged mice express multiple inhibitory receptors, providing evidence of the relationship between T-cell exhaustion and T-cell senescence. In this study, we showed that T-cell immunoglobulin and immunoreceptor tyrosine-based inhibitory motif (ITIM) domain (TIGIT), a novel co-inhibitory receptor, was upregulated in CD8 T cells of elderly adults. Aged TIGIT CD8 T cells expressed high levels of other inhibitory receptors including PD-1 and exhibited features of exhaustion such as downregulation of the key costimulatory receptor CD28, representative intrinsic transcriptional regulation, low production of cytokines, and high susceptibility to apoptosis. Importantly, their functional defects associated with aging were reversed by TIGIT knockdown. CD226 downregulation on aged TIGIT CD8 T cells is likely involved in TIGIT-mediated negative immune suppression. Collectively, our findings indicated that TIGIT acts as a critical immune regulator during aging, providing a strong rationale for targeting TIGIT to improve dysfunction related to immune system aging.
MeSH Terms
- Adult
- Aged
- Animals
- CD8-Positive T-Lymphocytes
- Humans
- Immunoglobulins
- Immunosenescence
- Mice
- Middle Aged
- Receptors, Immunologic
Keywords
TIGIT
- CD8 T cells
- T-cell immunosenescence
- aging
- co-inhibitory receptors
The innate and adaptive branches of the immune system display changes with aging, a fact referred to as immunosenescence. Furthermore, it has been established that adaptive immunity is more susceptible to age-related changes than innate immunity. The most prominent phenotypic changes that reflect the specific differentiation and role of each T cell subpopulation are two-fold. They are a decreased number of naïve T cells that parallels an increase in memory T cells, mainly in the cytotoxic CD8 T cell population, which can be subdivided into naïve, central, effector memory and TEMRA cells. The two main T cell properties that are the most affected with aging are the altered clonal expansion and decreased cytokine production, especially IL-2. These T cell functions have been shown to be affected in the early events of signaling. The aim of the present study was to investigate the influence of age on TCR- and CD28-dependent activation of the downstream signaling effectors Lck, SHP-1, Akt, PI3K p85α and mTOR in differentiated subpopulations of CD4 and CD8 T cells. Results showed that lymphocytes of elderly subjects were already in an activated state that could not be upregulated by external stimulation. Results also showed that the age-related signal transduction changes were more important than phenotype in the CD4 and CD8 T subpopulations. These observations suggested that age-related molecular and biochemical changes have a more significant influence on T cell functions than T cell phenotype.
MeSH Terms
- Adult
- Aged
- Aging
- CD28 Antigens
- CD4-Positive T-Lymphocytes
- CD8-Positive T-Lymphocytes
- Cell Differentiation
- Female
- Healthy Volunteers
- Humans
- Immunity, Innate
- Lymphocyte Activation
- Male
- Signal Transduction
- Young Adult
Keywords
- CD4( ) T cell subpopulations
- CD4( ) T cells
- CD8( ) T cell subpopulations
- CD8( ) T cells
- Signal transduction
- T cells
Behçet's disease (BD) is a chronic inflammatory disease characterized by recurrent mucocutaneous, ocular, and skin lesions. Immunosenescence is associated with increased susceptibility to infection and chronic low grade inflammation. This study aimed to investigate the differences in the frequencies of immunosenescent cells in the peripheral blood mononuclear cells (PBMCs) of patients with BD. PBMCs were isolated from age-matched patients with active BD (n = 19), inactive BD (n = 20), disease controls (DCs, n = 15) and healthy controls (HCs, n = 15). The frequencies of senescent CD4 T cells (CD3 CD4 CD27- CD28- cells), CD8 T cells (CD3 CD8 CD27- CD28- cells) and B cells (CD19 CD27- IgD- cells) were analyzed using flow cytometry. Senescence-associated β galactosidase activity was also measured in CD8 T cells using flow cytometry with 5-dodecanoylaminofluorescein di-β-D-galactopyranoside. Frequencies of senescent CD4 and CD19 cells were not significantly different between the groups. The frequency of senescent CD8 T cells was significantly higher in active BD than in DCs and HCs. C-reactive protein and erythrocyte sedimentation rate levels, which indicate disease activity, did not correlate with increased frequencies of immunosenescent cells. Steroid treatment, specific organ involvement, and HLA-B51 status did not have a significant influence on the frequencies of immunosenescent cells. Frequencies of senescence-associated β galactosidase CD8 T cells were significantly higher in active BD and inactive BD compared to DCs and HCs. There was an increased frequency of senescent CD8 T cells in the PBMCs of patients with BD.
MeSH Terms
- Adult
- B-Lymphocytes
- Behcet Syndrome
- CD4-Positive T-Lymphocytes
- CD8-Positive T-Lymphocytes
- Female
- Flow Cytometry
- HLA-B51 Antigen
- Humans
- Immunosenescence
- Male
- Middle Aged
Keywords
- Behcet’s disease
- Flow cytometry
- Immunosenescence
- Lymphocytes
- β-Galactosidase
The pioneering Swedish OCTO/NONA-Immune longitudinal studies led by Anders Wikby in Jönköping in the 1990s established a cluster of simple baseline immune parameters associated with excess mortality in 85 year-old non-institutionalized individuals over 2, 4 and 6-year follow-up. We dubbed this cluster the "Immune Risk Profile" (IRP) consisting of poor proliferative responses of peripheral blood mononuclear cells to T cell mitogens, accumulations of CD8 CD28- T-cells resulting in an inverted CD4:8 ratio, decreased amounts of B-cells, and seropositivity for Cytomegalovirus (CMV). The concept of the IRP has since been applied by others to many different populations in different circumstances and at different ages, but in general without specifically establishing whether the same risk factors were relevant in the tested subjects. However, our own later studies showed that risk factors in aged populations from The Netherlands and Belgium were markedly different, indicating that the IRP cannot simply be transferred between populations. Moreover, there was a striking sex difference in the Belgian study, which was the only one large enough to include sufficient numbers of old men. The reasons for these marked differences between populations which one might have assumed a priori to be quite similar to one another are not clear, and many candidates can be speculated upon, but the important lesson is that there is a marked context-dependency of immune biomarkers of ageing, suggesting that IRPs cannot be assumed to be identical in different populations.
MeSH Terms
- Aged, 80 and over
- B-Lymphocytes
- Belgium
- CD4-CD8 Ratio
- CD8-Positive T-Lymphocytes
- Cohort Studies
- Cytomegalovirus Infections
- Female
- Humans
- Immunosenescence
- Longitudinal Studies
- Male
- Mortality
- Netherlands
- Risk Factors
- Sweden
Keywords
- Cytomegalovirus
- Immune risk profile
- Immunosenescence
Polypoidal choroidal vasculopathy (PCV) and neovascular age-related macular degeneration (AMD) are prevalent age-related diseases characterized by exudative changes in the macula. Although they share anatomical and clinical similarities, they are also distinctly characterized by their own features, e.g. vascular abnormalities in PCV and drusen-mediated progression in neovascular AMD. PCV remains etiologically uncharacterized, and ongoing discussion is whether PCV and neovascular AMD share the same etiology or constitute two substantially different diseases. In this study, we investigated T-cell differentiation and aging profile in human patients with PCV, patients with neovascular AMD, and age-matched healthy control individuals. Fresh venous blood was prepared for flow cytometry to investigate CD4 and CD8 T-cell differentiation (naïve, central memory, effector memory, effector memory CD45ra ), loss of differentiation markers CD27 and CD28, and expression of aging marker CD56. Patients with PCV were similar to the healthy controls in all aspects. In patients with neovascular AMD we found significantly accelerated T-cell differentiation (more CD28 CD27 cells) and aging (more CD56 cells) in the CD8 T-cell compartment. These findings suggest that PCV and neovascular AMD are etiologically different in terms of T cell immunity, and that neovascular AMD is associated with T-cell immunosenescence.
MeSH Terms
- Aged
- Aged, 80 and over
- Biomarkers
- CD28 Antigens
- CD4-Positive T-Lymphocytes
- CD56 Antigen
- CD8-Positive T-Lymphocytes
- Case-Control Studies
- Cell Differentiation
- Cellular Senescence
- Choroidal Neovascularization
- Female
- Humans
- Immunosenescence
- Macular Degeneration
- Male
- Neovascularization, Pathologic
- Prospective Studies
- Tumor Necrosis Factor Receptor Superfamily, Member 7
Keywords
- T-cells
- age-related macular degeneration
- immunosenescence
- polypoidal choroidal vasculopathy
This paper was aimed to compare the effect of Buzhong Yiqi decoction containing Hedysari Radix or Astragali Radix on anti-immunosenescence effects in spleen lymphocytes of senescence accelerated mouse 8 (SAMP8). The effect of the serums on the proliferation of spleen T lymphocytes in SAMP8 mice induced by ConA was tested by MTT. The effect of the serums on the T lymphocytes subsets of SAMP8 mice was measured by flow cytometry. ELISA was used to detect the level of IL-2 and IFN-γ in the culture supernatants of spleen lymphocytes. The effect of the serums on the expression of CD28 mRNA in spleen T lymphocytes was detected by fluorescent quantitative PCR. Western blot was used to detect the expression of CD28 protein in spleen T lymphocytes of SAMP8 mice. Both the serums of Buzhong Yiqi decoctions containing Hedysari Radix or Astragali Radix improved the proliferation of T lymphocytes in SAMP8 mice. Both the serums had no obvious effect on the differentiation of spleen T lymphocytes'subsets in SAMP8 mice. Both the serums increased the content of IL-2 and INF-γ in the culture supernatants of spleen lymphocytes. And for the content of IL-2, the serum of Buzhong Yiqi decoction with Hedysari Radix was better（P<0.05）. Both the serums improved the expression of CD28 mRNA in spleen T lymphocytes of SAMP8 mice. And the effect of Hedysari Radix group was better than that of Astragalus Radix group（P<0.05）. Both the serums improved the expression of CD28 protein in spleen T lymphocytes of SAMP8 mice. The role of the serums containing Buzhong Yiqi decoction with Astragalus Radix and the decoction with Hedysari Radix in anti-immunosenescence was through the effect of the CD28. And the effect of Hedysari Radix group was better than that of Astragalus Radix group on improved the expression of CD28 mRNA in T lymphocytes of SAMP8 mice. Astragalus Radix and Hedysari Radix could swap in the aspect of anti-immunosenescence.
MeSH Terms
- Animals
- Astragalus Plant
- Drugs, Chinese Herbal
- Fabaceae
- Immunosenescence
- Lymphocytes
- Mice
- Spleen
Keywords
- Astragali Radix
- Buzhong Yiqi decoction
- Hedysari Radix
- SAMP8 mice
- anti-immunosenescence
Arterial stiffness is a well-known predictor of future cardiovascular events. Search for the underlying mechanism of arterial stiffening is still under way. We investigated the relationship between arterial stiffness and cytomegalovirus infection in terms of T-cell senescence. Arterial stiffness was evaluated using pulse wave velocity measurements in 415 Koreans (age 59±12 years). We also investigated the frequency of CD57 or CD28 senescent T cells in peripheral blood lymphocytes and analyzed which immune parameters were correlated with pulse wave velocity. Furthermore, cytomegalovirus-specific T cells were stimulated with overlapping peptides covering pp65 protein, and T-cell function was evaluated by intracellular cytokine staining of interferon-γ, tumor necrosis factor-α, and CD107a. In a multivariate analysis, it was found that the frequency of CD57 cells in the CD8 T-cell subset was independently correlated with pulse wave velocity after adjusting for traditional cardiovascular risk factors such as age, sex, diabetes mellitus history, smoking history, body mass index, blood pressure, serum creatinine, high-density lipoprotein cholesterol, and high-sensitivity C-reactive protein. Cytomegalovirus pp65-specific T cells were more frequently observed in the CD8 CD57 population than in the CD8 CD57 population, and multivariate analysis revealed that the frequency of cytomegalovirus pp65-specific interferon-γ , tumor necrosis factor-α , or CD107a cells in the CD8 T-cell subset was independently correlated with pulse wave velocity as well. We demonstrate that arterial stiffness is associated with senescent CD57 T cells and CMV pp65-specific T cells in the CD8 T-cell subset. The precise role of cytomegalovirus-specific, senescent T cells in vascular aging needs to be further investigated.
MeSH Terms
- Adult
- Aged
- Aged, 80 and over
- CD57 Antigens
- CD8-Positive T-Lymphocytes
- Cell Separation
- Cells, Cultured
- Cytomegalovirus
- Cytomegalovirus Infections
- Female
- Flow Cytometry
- Host-Pathogen Interactions
- Humans
- Immunosenescence
- Linear Models
- Male
- Middle Aged
- Multivariate Analysis
- Phosphoproteins
- Pulse Wave Analysis
- Republic of Korea
- Vascular Stiffness
- Viral Matrix Proteins
- Young Adult
Keywords
- T cells
- arterial stiffness
- cytomegalovirus
- immunosenescence
- pulse wave velocity
Ageing of the human immune system, or immunosenescence, is characterised by distinct changes in the proportion of the various cell types, e.g., increase of the CD14 monocytic cells, decrease of CD19 B lymphocytes, and changes in T cell subpopulations, namely increase of CD4 and CD8 cells which have lost the costimulatory CD28 antigen. Currently, it is believed that the lifelong antigenic burden may be one of the inducers of immunosenescence. Thus far, only one exogenous stimulus, cytomegalovirus infection, has shown to be a major factor in this respect. To find other possible candidates, we evaluated the role of the evolutionary youngest group of human endogenous retroviruses, namely HERV-K(HML-2), on immunosenescence. HERVs exist in the genome as proviruses, but their activation has been detected in several immunopathologic conditions. The expression of HERV-K(HML-2) env was observed to be lower in the peripheral blood mononuclear cells of nonagenarians (n=61) than in those of young controls (n=37). These mRNA levels did not correlate with the age-associated differences in the proportions of CD14 , CD4 CD28- and CD8 CD28- cells, but in the case of CD19 B cells a strong positive correlation was observed in the nonagenarians. Thus, these data suggest that HERVs do not function as antigenic drivers of immunosenescence. On the contrary, expression of HERV-K(HML-2) env is associated with more youthful levels of B cells.
MeSH Terms
- Adult
- Aged, 80 and over
- B-Lymphocytes
- Biomarkers
- Endogenous Retroviruses
- Female
- Finland
- Humans
- Immunosenescence
- Leukocytes, Mononuclear
- Male
- Prospective Studies
- Proviruses
- Viral Envelope Proteins
- Young Adult
Keywords
- Ageing
- B cells
- HERV-K(HML-2)
- Human endogenous retrovirus
- Immunosenescence
Immunosenescence has been scrutinized in detail, and evidence that inflammation and ageing are interrelated is consistent. Still, a gold standard for assessing the biological age of the immune function in an individual patient is lacking, so that immunosenescence is still not a quantifiable criterion in clinical decision-making processes. This review highlights recent (partly ongoing) studies into biomarkers of inflammation to assess immunosenescence, including large-scale studies, and quotes expert opinion statements. Markers of basal inflammation frequently used include interleukin-6, tumor necrosis factor-α and receptors p55 and p75, C-reactive protein and cytomegalovirus antibody levels. Some cellular markers are particularly advocated to reflect age-related decay of specific immunity, namely the decrease of naive T cells, especially CD8cells, and accumulations of memory T cells, especially late-stage differentiated CD8 cells; the loss of CD28 on lymphocytes is also taken as a biomarker of immunosenescence. Substantial progress has been made in both understanding and phenotyping immunosenescence and inflammageing. The diagnosis of the degree of immunosenescence in the individual patient, however, has not yet been standardized.
MeSH Terms
- Aged
- Aged, 80 and over
- Animals
- Biomarkers
- Biomedical Research
- Geriatric Assessment
- Humans
- Immunosenescence
- Inflammation Mediators
To evaluate the consequences of plasma from individuals with obesity on parameters associated with immunosenescence in unrelated healthy peripheral blood mononuclear cells (PBMC). Freshly isolated PBMC were incubated in media supplemented with 10% of plasma from individuals with obesity or control subjects for the first 4 hours of 24 to 120 hours of culture. Plasma from individuals with obesity modulated the phenotype of healthy PBMC, leading to a higher rate of apoptosis, lower amounts of phospho-γH2AX and -p53, and mitochondrial dysfunction. After 120 hours, there was a higher secretion of inflammatory cytokines IL-1β and IL-8. CD8 T lymphocytes presented decreased expression of CD28, which is associated with the immunosenescent phenotype. CD14 macrophages showed increased expression of CD80 and CD206, suggesting a modulation in the activation of macrophages. These results demonstrate that chronic systemic inflammation observed in obesity induces dysfunctional features in PBMC that are consistent with premature immunosenescence.
MeSH Terms
- Adult
- Apoptosis
- CD8-Positive T-Lymphocytes
- Culture Media
- Female
- Humans
- Immunosenescence
- Inflammation
- Interleukin-1beta
- Interleukin-8
- Leukocytes, Mononuclear
- Macrophages
- Male
- Obesity
- Serum
- Signal Transduction
Cytomegalovirus (CMV) has been described as a contributor to immunosenescence, thus exacerbating age-related diseases. In persons with latent CMV infection, the CD8 T cell compartment is irreversibly changed, leading to the accumulation of highly differentiated virus-specific CD8 T cells in the peripheral blood. The bone marrow (BM) has been shown to play a major role in the long-term survival of antigen-experienced T cells. Effector CD8 T cells are preferentially maintained by the cytokine IL-15, the expression of which increases in old age. However, the impact of CMV on the phenotype of effector CD8 T cells and on the production of T cell survival molecules in the BM is not yet known. We now show, using BM samples obtained from persons who underwent hip replacement surgery because of osteoarthrosis, that senescent CD8 T cells with a bright expression of CD45RA and a high responsiveness to IL-15 accumulate in the BM of CMV-infected persons. A negative correlation was found between CMV antibody (Ab) titers in the serum and the expression of CD28 and IL-7Rα in CD8 [Formula: see text] cells. Increased IL-15 mRNA levels were observed in the BM of CMV compared to CMV persons, being particularly high in old seropositive individuals. In summary, our results indicate that a BM environment rich in IL-15 may play an important role in the maintenance of highly differentiated CD8 T cells generated after CMV infection.
Keywords
- aging
- bone marrow
- cytomegalovirus
- immunosenescence
- senescence
A pectic polysaccharide (named as CPP1c) extracted from Codonopsis pilosula was evaluated for its structural features and potential of immune-modulating activities in an aging mouse model of senescence accelerated mouse prone 8 (SAMP8) in vitro and in vivo. The relative molecular weight and the absolute molecular weight of CPP1c were 1.26×10 Da and 1.49×10 Da, respectively. Investigation of structural features by a combination of chemical and instrumental analysis showed CPP1c was composed of →1)-α-l-Rhap-(2,4→, →1)-α-l-Araf-(5→, →1)-α-d-Galp-(6→ and →1)-α-d-GalpA-(4→ in a molar ratio of 3:1:2:33. CPP1c could promote lymphocyte proliferation, modulate the percentage of CD4 , CD8 , CD28 and CD152 T cells and enhance the production of IL-2, TNF-α and IFN-γ. Moreover, PCR assay revealed CPP1c augmented the expressions of CD28, PI3K and p38MAPK mRNA, and the increase of protein expressions of the same genes was also confirmed by western blot analyses. In addition, CPP1c had the potential of promoting the homing of lymphocytes. Taking all factors into consideration, we deduced CPP1c might exert its immunostimulating potency via promoting T cell activation by TCR/CD28 signaling pathways.
MeSH Terms
- Animals
- Codonopsis
- Cytokines
- Immunologic Factors
- Male
- Methylation
- Mice
- Monosaccharides
- Pectins
- T-Lymphocyte Subsets
Keywords
- Codonopsis pilosula pectic polysaccharide
- Immunomodulatory activities
- Senescence accelerated mouse prone 8 (SAMP8)
Cytomegalovirus (CMV), a member of the β-herpesvirus family, is a major complicating infection in transplant patients. CMV latency has a long-term impact on CD8 T-cell differentiation. It is unclear, however, whether this effect can be detected in one-year period. To investigate this, we analyzed the remodeling of the CD8 T-cell compartment during the first year after solid organ transplantation. A total of 55 kidney or lung transplant patients were recruited. CD8 T-cell subsets were prospectively analyzed at pretransplant, at 3 or 6months and 12months after transplantation (mo post-Tx). A significant increase in the frequency of CD27 CD28 CD8 T cells (from 32.8% to 42.3%; p=0.014) was observed from pretransplant to 12mo post-Tx. Further analysis, however, showed that the largest expansion was observed from 3/6 to 12mo post-Tx whereas small non-significant variations were observed from pretransplant to 3/6mo post-Tx. The adjusted analysis showed that age and CMV seropositivity were statistically associated with the baseline frequency of CD27 CD28 CD8 T cells. Additionally, CMV replication was related to the posttransplant expansion of this subpopulation, since it was not observed in patients without CMV viremia (24% vs. 4.2%). The results indicate that the expanded frequency associated with late CMV replication is additive to the baseline frequency related to aging and CMV seropositivity. If the expanded frequency remains at this high level for a long period it might have clinical consequences related to the control of future reactivations of CMV or of other related viruses.
MeSH Terms
- Adult
- Age Factors
- Aging
- CD8-Positive T-Lymphocytes
- Cell Differentiation
- Cell Proliferation
- Cytomegalovirus
- Cytomegalovirus Infections
- Female
- Follow-Up Studies
- Host-Pathogen Interactions
- Humans
- Interferon-gamma
- Kidney Transplantation
- Longitudinal Studies
- Lung Transplantation
- Lymphocyte Activation
- Male
- Middle Aged
- Prospective Studies
- Spain
- Time Factors
- Treatment Outcome
- Virus Activation
- Virus Replication
Keywords
- CD8( ) T cells
- Cytomegalovirus
- Interferon-gamma
- Late-differentiated cells
- QuantiFERON-CMV test
- Transplantation
Delayed immunologic aging is purported to be a major mechanism through which calorie restriction (CR) exerts its anti-aging effects in non-human species. However, in non-obese humans, the effect of CR on the immune system has been understudied relative to its effects on the cardiometabolic system. To examine whether CR is associated with delayed immunologic aging in non-obese humans. We tested whether long-term CR practitioners (average 10.03 years of CR) evidenced decreased expression of T cell immunosenescence markers and longer immune cell telomeres compared to gender-, race/ethnicity-, age-, and education-matched "healthy" Body Mass Index (BMI) and "overweight"/"obese" BMI groups. Long-term human CR practitioners had lower BMI ([i]p[/i] < 0.001) and fasting glucose ([i]p[/i] < 0.001), as expected. They showed similar frequencies of pre-senescent cells (CD8 CD28 T cells and CD57 and PD-1 expressing T cells) to the comparison groups. Even after adjusting for covariates, including cytomegalovirus status, we observed shorter peripheral blood mononuclear cell telomeres in the CR group ([i]p[/i] = 0.012) and no difference in granulocyte telomeres between groups ([i]p[/i] = 0.42). We observed no clear evidence that CR as it is currently practiced in humans delays immune aging related to telomere length or T cell immunosenescent markers.
Keywords
- Caloric restriction
- T-cells
- cellular aging
- eating behavior
- immunosenescence
- telomeres
Premature senescence of lymphocytes is a hallmark of inflammatory rheumatic diseases such as rheumatoid arthritis (RA). Early T-cell aging affects conventional T-cells but is presumably not limited to this cell population; rather it might also occur in the regulatory T-cells (Tregs) compartment. In RA, Tregs fail to halt aberrant immune reactions and disease progression. Whether this is associated with early Treg senescence leading to phenotypic and functional changes of this subset is elusive so far. Eighty-four RA patients and 75 healthy controls were prospectively enrolled into the study. Flow cytometry, magnetic-associated cell sorting, and cell culture experiments were performed for phenotypic and functional analyses of Treg subsets. T-cell receptor excision circle (TREC) levels and telomere lengths were determined using RT-PCR. In this paper, we describe the novel CD4 FoxP3 CD28 T-cell subset (CD28 Treg-like cells) in RA patients revealing features of both Tregs and senescent T-cells: Treg surface/intracellular markers such as CD25, CTLA-4, and PD-1 as well as FOXP3 were all expressed by CD28 Treg-like cells, and they yielded signs of premature senescence including reduced TREC levels and an accumulation of γH2AX. CD28 Treg-like could be generated [i]in vitro[/i] by stimulation of (CD28 ) Tregs with TNF-α. CD28 Treg-like cells insufficiently suppressed the proliferation of effector T-cells and yielded a pro-inflammatory cytokine profile. In conclusion, we describe a novel T-cell subset with features of Tregs and senescent non-Tregs. These cells may be linked to an aberrant balance between regulatory and effector functions in RA.
Keywords
- aging
- autoimmunity
- immunosenescence
- premature
- regulatory T cells
- rheumatoid arthritis
The purpose of this study was to investigate the effects of melatonin on selected biomarkers of innate and humoral immune response as well as the antioxidant/oxidant status (superoxide dismutase-SOD and reduced glutathione levels (GSH) to understand whether age-related changes would influence the development of acute Trypanosoma cruzi (T. cruzi) infection. Young- (5 weeks) and middle-aged (18 months) Wistar rats were orally treated with melatonin (gavage) (05 mg/kg/day), 9 days after infection. A significant increase in both SOD activity and GSH levels was found in plasma from all middle-aged melatonin-treated animals. Melatonin triggered enhanced expression of major histocompatibility class II (MHC-II) antigens on antigen-presenting cell (APC) and peritoneal macrophages in all treated animals. High levels of CD4 CD28-negative T cells (*P<.05) were detected in middle-aged control animals. Melatonin induced a significant reduction (***P<.001) in CD28-negative in CD4 and CD8 T cells in middle-aged control animals. Contrarily, the same group displayed upregulated CD4 CD28 T and CD8 CD28 T cells. Melatonin also triggered an upregulation of CD80 and CD86 expression in all young-treated groups. Significant percentages of B and spleen dendritic cells in middle-aged infected and treated animals were observed. Our data reveal new features of melatonin action in inhibiting membrane lipid peroxidation, through the reduction in 8-isoprostane, upregulating the antioxidant defenses and triggering an effective balance in the antioxidant/oxidant status during acute infection. The ability of melatonin to counteract the immune alterations induced by aging added further support to its use as a potential therapeutic target not only for T. cruzi infection but also for other immunocompromised states.
MeSH Terms
- Aging
- Animals
- Antioxidants
- CD28 Antigens
- Chagas Disease
- Macrophages, Peritoneal
- Male
- Melatonin
- Oxidative Stress
- Oxidoreductases
- Rats
- Rats, Wistar
Keywords
Trypanosoma cruzi
- antioxidant protection
- immune response
- melatonin
The present investigation assessed the potential of green tea phytochemical epigallocatechin-3-gallate (EGCG) in alleviating age-associated aberrations in immunity, hypothalamus-pituitary-adrenal (HPA) axis and redox homeostasis using 16 months old male Swiss albino mice. Four groups of animals (n = 6 per group) were supplemented with either aqueous EGCG at 25, 50 and 100 mg/kg/animal or vehicle control for 6 weeks. A concurrent analysis of CD4 and CD8 lymphocytes in splenocytes, differential leucocyte population, T cell differentiation markers in peripheral blood mononuclear cells (PBMCs), neutrophil functions, immunoglobulins profile in intestine, circulatory HPA axis hormonal levels as well as inflammatory and oxidative stress in the liver was performed. We observed a remarkable increase in plasma dehydroepiandrosterone (DHEA) levels of 100 mg EGCG fed animals while eosinophils and monocytes counts in blood increased. EGCG consumption increased the fraction of CD3 CD8 cells in splenocytes and CD28 expression on PBMCs. The immunoglobulins profile revealed decreased production of secretory IgA, IgE and IgG1/IgG2a ratio. Liver extracts showed increase in superoxide dismutase activity and total antioxidant capacity while lipid peroxidation along with inflammatory markers (IL-6 and TNF-α) decreased. Our results collectively show that EGCG consumption during aging strengthens systemic immunity by enhancing cellular immune response and simultaneously attenuating antibody response aided by an increase in adrenal DHEA production. Thus, consumption of green tea may be beneficial in alleviating some of the deleterious aspects of aging and immunosenescence in elderly.
MeSH Terms
- Aging
- Animals
- Antibody Formation
- Antioxidants
- Catechin
- Dehydroepiandrosterone
- Dose-Response Relationship, Drug
- Hypothalamo-Hypophyseal System
- Immunity, Cellular
- Immunoglobulins
- Leukocyte Count
- Liver
- Male
- Mice
- Oxidative Stress
- Pituitary-Adrenal System
- Real-Time Polymerase Chain Reaction
- Tea
Keywords
- Antibodies
- DHEA
- EGCG
- Eosinophils
- Redox
Ageing is associated with changes in the peripheral T cell immune system, which can be influenced significantly by latent cytomegalovirus (CMV) infection. To what extent changes in circulating T cell populations correlate with T cell composition of the lymph node (LN) is unclear, but is crucial for a comprehensive understanding of the T cell system. T cells from peripheral blood (PB) and LN of end-stage renal disease patients were analysed for frequency of recent thymic emigrants using CD31 expression and T cell receptor excision circle content, relative telomere length and expression of differentiation markers. Compared with PB, LN contained relatively more CD4 than CD8 T cells (P < 0·001). The percentage of naive and central memory CD4 and CD8 T cells and thymic output parameters showed a strong linear correlation between PB and LN. Highly differentiated CD28 T cells, being CD27 , CD57 or programmed death 1 (PD-1 ), were found almost exclusively in the circulation but not in LN. An age-related decline in naive CD4 and CD8 T cell frequency was observed (P = 0·035 and P = 0·002, respectively) within LN, concomitant with an increase in central memory CD8 T cells (P = 0·033). Latent CMV infection increased dramatically the frequency of circulating terminally differentiated T cells, but did not alter T cell composition and ageing parameters of LN significantly. Overall T cell composition and measures of thymic function in PB and LN are correlated strongly. However, highly differentiated CD28 T cells, which may comprise a large part of circulating T cells in CMV-seropositive individuals, are found almost exclusively within the circulation.
MeSH Terms
- Aged
- Aging
- Antigens, Differentiation, T-Lymphocyte
- CD4-Positive T-Lymphocytes
- CD8-Positive T-Lymphocytes
- Cell Differentiation
- Cytomegalovirus Infections
- Female
- Humans
- Immunologic Memory
- Kidney Failure, Chronic
- Lymph Nodes
- Lymphocyte Activation
- Lymphocyte Count
- Male
- Middle Aged
- Platelet Endothelial Cell Adhesion Molecule-1
- Virus Latency
Keywords
- T cells
- ageing
- end-stage renal disease
- lymph node
- peripheral blood
Sepsis is a leading cause of mortality in intensive care units, and is more common in the geriatric population. The control of hyperinflammation has been suggested as a therapeutic approach in sepsis, but to date clinical trials utilizing this strategy have not lead to an effective treatment. In addition to hyperinflammation, patients with sepsis often experience a state of immunosuppression, which serves as an important determinant for increased morbidity and mortality. We previously used aged animals to demonstrate the effectiveness of combined treatment with human ghrelin (Ghr) and human growth hormone (GH) in improving organ injury and survival in septic animals. Here, we hypothesized that combined treatment with Ghr and GH could improve immune function in septic aged animals. Male 24-month-old rats were subjected to cecal ligation and puncture (CLP) for sepsis induction. Human Ghr (80nmol/kg BW) plus GH (50μg/kg BW) or vehicle (normal saline) was administrated subcutaneously at 5h after CLP. The ex vivo production of TNF-α, IL-6 and IL-10 to LPS-stimulation, as well as TNF-α, IL-6, IL-10 and IFN-γ production to anti-CD3/anti-CD28 antibody-stimulation, in splenocytes isolated 20h after CLP, was significantly decreased compared to production of these cytokines in splenocytes from sham animals. The production of cytokines from splenocytes isolated from septic animals that received the combined treatment, however, was significantly higher than from those isolated from vehicle-treated septic animals. Combined treatment prevented the loss of splenic CD4 and CD8 T cells in septic aged rats, and reduced lymphocyte apoptosis. Combined treatment also inhibited an increase in the regulatory T cell (T ) population and expression of the immune co-inhibitory molecule PD-1 in the spleens of septic aged rats. In contrast, expression of HLA-DR was increased after combined treatment with Ghr and GH. Based on these findings, we conclude that co-administration of Ghr and GH is a promising therapeutic tool for reversing immunosuppression caused by sepsis in the geriatric population. This article is part of a Special Issue entitled: Immune and Metabolic Alterations in Trauma and Sepsis edited by Dr. Raghavan Raju.
MeSH Terms
- Aging
- Animals
- Apoptosis
- CD8-Positive T-Lymphocytes
- Cytokines
- Ghrelin
- Human Growth Hormone
- Humans
- Immunosuppression
- Male
- Programmed Cell Death 1 Receptor
- Rats
- Rats, Inbred F344
- Sepsis
- T-Lymphocytes, Regulatory
Keywords
- Aging
- Ghrelin
- Growth hormone
- Immunosuppression
- Sepsis
The ability of the human immune system to protect against infectious disease declines with age and efficacy of vaccination reduces significantly in the elderly. Aging of the immune system, also termed as immunosenescence, involves many changes in human T cell immunity that is characterized by a loss in naïve T cell population and an increase in highly differentiated CD28- memory T cell subset. There is extensive data showing that latent persistent human cytomegalovirus (HCMV) infection is also associated with age-related immune dysfunction in the T cells, which might enhance immunosenescence. Understanding the molecular mechanisms underlying age-related and HCMV-related immunosenescence is critical for the development of effective age-targeted vaccines and immunotherapies. In this review, we will address the role of both aging and HCMV infection that contribute to the T cell senescence and discuss the potential molecular mechanisms in aged T cells.
Keywords
- HCMV infection
- aging
- epigenetic regulation
- immunosenescence
- naive and memory T cells
- vaccination
The aim of this study is to evaluate the age related changes of T lymphocyte subsets in C57BL/6 mice and immune function. Multi-color immunofluorescence techniques that were used to analyse relative numbers of T lymphocyte subsets include CD4 , CD8 , naive and memory CD4 and CD8 , CD8 CD28 T cells in peripheral blood of C57BL/6 mice from different age groups (Group I: 2 months old; Group II: 7 months old; Group III: 21 months old); Splenocytes isolated from different group mice were stimulated with Con A to evaluate the proliferative ability. Compared with group I, group II had a significant reduction in the percentage of CD4 , naive CD4 and CD8 T cells and an increase in the percentage of CD8 T cells, while group III had a significant reduction in the percentage of CD4 , naive CD4 and CD8 T cells and increase in the percentage of CD8 , memory CD4 and CD8 T cells in peripheral blood. Compared with group II, group III had a significant reduction in the percentage of naive CD8 T cells and increase in the percentage of memory CD4 and CD8 , CD8 CD28 T cells in peripheral blood. The T lymphocyte proliferation in vitro showed that groups II and III had a lower proliferative capacity than group I, between groups II and III, there was not a significant difference. We provide relative values for the T lymphocyte subsets in the different age groups of C57BL/6 mice. The immune system began aging at 7 months old in C57BL/6 mice under a specific pathogen free environment.
Keywords
- Aging
- C57BL/6 mice
- Immunosenescence
- T lymphocyte subsets
Human natural killer (NK)-like CD8 T-cells are singular T-cells that express both T and NK cell markers such as CD56; their frequencies depend on their differentiation and activation during their lifetime. There is evidence of the presence of these innate CD8 T-cells in the human umbilical cord, highlighting the necessity of investigating whether the NK-like CD8 T-cells arise in the early stages of life (gestation). Based on the presence of cell surface markers, these cells have also been referred to as CD8 KIR T-cells, innate CD8 T-cells, CD8 CD28 KIR T-cells or NKT-like CD8 CD56 cells. However, the functional and co-signaling significance of these NK cell receptors on NK-like CD8 T-cells is less clear. Also, the diverse array of costimulatory and co-inhibitory receptors are spatially and temporally regulated and may have distinct overlapping functions on NK-like CD8 T-cell priming, activation, differentiation, and memory responses associated with different cell phenotypes. Currently, there is no consensus regarding the functional properties and phenotypic characterization of human NK-like CD8 T-cells. Environmental factors, such as aging, autoimmunity, inflammation, viral antigen re-exposure, or the presence of persistent tumor antigens have been shown to allow differentiation ("adaptation") of the NK-like CD8 T-cells; the elucidation of this differentiation process and a greater understanding of the characteristics of these cells could be important for their eventual in potential therapeutic applications aimed at improving protective immunity. This review will attempt to elucidate an understanding of the characteristics of these cells with the goal toward their eventual use in potential therapeutic applications aimed at improving protective immunity.
Keywords
- CD56
- CMV
- NK-like CD8 T-cells
- T-cell differentiation
- aging
- immunosenescence
- memory
- natural killer receptors
The bone marrow (BM) plays a key role in the long-term maintenance of immunological memory. However, the impact of aging on the production of survival factors for effector/memory T cells and plasma cells in the human BM has not been studied. We now show that the expression of molecules involved in the maintenance of immunological memory in the human BM changes with age. While IL-15, which protects potentially harmful CD8 CD28 senescent T cells, increases, IL-7 decreases. IL-6, which may synergize with IL-15, is also overexpressed. In contrast, a proliferation-inducing ligand, a plasma cell survival factor, is reduced. IFN-y, TNF, and ROS accumulate in the BM in old age. IL-15 and IL-6 expression are stimulated by IFN-y and correlate with ROS levels in BM mononuclear cells. Both cytokines are reduced by incubation with the ROS scavengers N-acetylcysteine and vitamin C. IL-15 and IL-6 are also overexpressed in the BM of superoxide dismutase 1 knockout mice compared to their WT counterparts. In summary, our results demonstrate the role of inflammation and oxidative stress in age-related changes of immune cell survival factors in the BM, suggesting that antioxidants may be beneficial in counteracting immunosenescence by improving immunological memory in old age.
MeSH Terms
- Acetylcysteine
- Aging
- Animals
- Ascorbic Acid
- Bone Marrow Cells
- CD8-Positive T-Lymphocytes
- Cell Survival
- Cells, Cultured
- Cytokines
- Free Radical Scavengers
- Humans
- Immunologic Memory
- Immunosenescence
- Inflammation
- Male
- Mice
- Mice, Inbred C57BL
- Mice, Knockout
- Reactive Oxygen Species
- Superoxide Dismutase-1
Keywords
- Aging
- Bone marrow
- Immunological memory
- Immunosenescence
- ROS
The Nijmegen breakage syndrome (NBS) is an inherited genetic disorder characterized by a typical facial appearance, microcephaly, growth retardation, immunodeficiency, and a strong predisposition to malignancies, especially of lymphoid origin. NBS patients have a mutation in the NBN gene which involves the repair of DNA double-strand breaks (DSBs). Here we studied the peripheral T cell compartment of NBS patients with a focus on immunological senescence. The absolute numbers and frequencies of the different T cell subsets were determined in NBS patients from young age till adulthood and compared to age-matched healthy individuals (HI). In addition, we determined the expression of senescent T cell markers and the signal joint T cell receptor excision circles (sjTRECs) content. Our results demonstrate that NBS patients have reduced T cell numbers. NBS patients showed lower numbers of αβ T cells, but normal γδ T cell numbers compared to HI. Concerning the αβ T cells, both CD4 as well as CD8 T cells were excessively reduced in numbers compared to aged-matched HI. In addition, NBS patients showed higher frequencies of the more differentiated T cells expressing the senescent cell marker CD57 and did not express co-stimulatory molecule CD28. These effects were already present in the youngest age group. Furthermore, NBS patients showed lower sjTREC content in their T cells possibly indicative of a lower thymic output. We conclude that circulating T cells from NBS patients show signs of a senescent phenotype which is already present from young age on and which might explain their T cell immune deficiency.
MeSH Terms
- Adolescent
- Adult
- B-Lymphocyte Subsets
- Biomarkers
- Cellular Senescence
- Child
- Child, Preschool
- Female
- Humans
- Immunophenotyping
- Infant
- Lymphocyte Count
- Male
- Mutation
- Nijmegen Breakage Syndrome
- Phenotype
- Receptors, Antigen, T-Cell
- Receptors, Antigen, T-Cell, alpha-beta
- Receptors, Antigen, T-Cell, gamma-delta
- Recombination, Genetic
- T-Lymphocyte Subsets
- Young Adult
Keywords
- CD28null
- NBS
- T cells
- senescence
- sjTREC
Aging is associated with a progressive loss of the CD28 costimulatory molecule in CD4 lymphocytes (CD28 T cells), which is accompanied by the acquisition of new biological and functional properties that give rise to an impaired immune response. The regulatory mechanisms that govern the appearance and function of this cell subset during aging and in several associated inflammatory disorders remain controversial. Here, we present the whole-genome DNA methylation and gene expression profiles of CD28 T cells and its CD28 counterpart. A comparative analysis revealed that 296 genes are differentially methylated between the two cell subsets. A total of 160 genes associated with cytotoxicity (e.g. GRZB, TYROBP, and RUNX3) and cytokine/chemokine signaling (e.g. CX3CR1, CD27, and IL-1R) are demethylated in CD28 T cells, while 136 de novo-methylated genes matched defects in the TCR signaling pathway (e.g. ITK, TXK, CD3G, and LCK). TCR-landscape analysis confirmed that CD28 T cells have an oligo/monoclonal expansion over the polyclonal background of CD28 T cells, but feature a Vβ family repertoire specific to each individual. We reported that CD28 T cells show a preactivation state characterized by a higher level of expression of inflammasome-related genes that leads to the release of IL-1β when activated. Overall, our results demonstrate that CD28 T cells have a unique DNA methylation landscape, which is associated with differences in gene expression, contributing to the functionality of these cells. Understanding these epigenetic regulatory mechanisms could suggest novel therapeutic strategies to prevent the accumulation and activation of these cells during aging.
MeSH Terms
- Apoptosis
- CD28 Antigens
- CD4 Antigens
- CD4-Positive T-Lymphocytes
- Cellular Senescence
- CpG Islands
- Cytotoxicity, Immunologic
- DNA Methylation
- Gene Expression Regulation
- Genome, Human
- Humans
- Immunity
- Inflammasomes
- Phenotype
- Receptors, Antigen, T-Cell
- Reproducibility of Results
- Signal Transduction
Keywords
- CD4 CD28null T cells
- DNA methylation
- TCR signaling
- aging
- gene expression
- inflammation
We analyzed gene expression profiles of young and aged mouse CD8 T cells specific for the nucleoprotein (NP) of influenza A/PR8/34 virus. CD8 T cells were stimulated either by the NP antigen expressed in its native form or fused into the herpes virus (HSV)-1 glycoprotein D (gD) protein, which blocks signaling through the immunoinhibitory B and T lymphocyte attenuator (BTLA) and CD160 pathways. We show that NP-specific CD8 T cells from aged mice exhibit numerous differences in gene expression compared to NP-specific CD8 T cells from young mice, including a significant reduction of expression in genes involved in T cell receptor (TcR) and CD28 signaling. We also show that these changes can be reversed in a sub-population (~50%) of the aged mice by a BTLA/CD160 checkpoint blockade. These results suggest that BTLA/CD160 checkpoint blockade has potential value as a vaccine additive to induce better CD8 T cell responses in the aged.
MeSH Terms
- Aging
- Animals
- Antigens, CD
- CD8-Positive T-Lymphocytes
- Female
- GPI-Linked Proteins
- Gene Expression Regulation
- Influenza A virus
- Influenza Vaccines
- Mice
- Mice, Inbred C57BL
- Orthomyxoviridae Infections
- Receptors, Immunologic
- Transcriptome
- Vaccination
Keywords
- BTLA/CD160
- CD8 cells
- aging
- gene expression
- vaccination
Aging affects negatively the immune system, defined as immunosenescence, which increases the susceptibility of elderly persons to infection, autoimmune disease, and cancer. There are strong indications that physical exercise in elderly persons may prevent the age-related decline in immune response without significant side effects. Consequently, exercise is being considered as a safe mode of intervention to reduce immunosenescence. The aim of this review was to appraise the existing evidence regarding the impact of exercise on surface markers of cellular immunosenescence in either young and old humans or animals. PubMed and Web of Science were systematically screened, and 28 relevant articles in humans or animals were retrieved. Most of the intervention studies demonstrated that an acute bout of exercise induced increases in senescent, naïve, memory CD4 and CD8 T-lymphocytes and significantly elevated apoptotic lymphocytes in peripheral blood. As regards long-term effects, exercise induced increased levels of T-lymphocytes expressing CD28 in both young and elderly subjects. Few studies found an increase in natural killer cell activity following a period of training. We can conclude that exercise has considerable effects on markers of cellular aspects of the immune system. However, very few studies have been conducted so far to investigate the effects of exercise on markers of cellular immunosenescence in elderly persons. Implications for immunosenescence need further investigation.
MeSH Terms
- Animals
- Biomarkers
- Exercise
- Humans
- Immunosenescence
- Physical Conditioning, Animal
Keywords
- Elderly
- Exercise
- Immunosenescence
- Surface marker
The goal of annual influenza vaccination is to reduce mortality and morbidity associated with this disease through the generation of protective immune responses. The objective of the current study was to examine markers of immunosenescence and identify immunosenescence-related differences in gene expression, gene regulation, cytokine secretion, and immunologic changes in an older study population receiving seasonal influenza A/H1N1 vaccination. Surprisingly, prior studies in this cohort revealed weak correlations between immunosenescence markers and humoral immune response to vaccination. In this report, we further examined the relationship of each immunosenescence marker (age, T cell receptor excision circle frequency, telomerase expression, percentage of CD28 CD4 T cells, percentage of CD28 CD8 T cells, and the CD4/CD8 T cell ratio) with additional markers of immune response (serum cytokine and chemokine expression) and measures of gene expression and/or regulation. Many of the immunosenescence markers indeed correlated with distinct sets of individual DNA methylation sites, miRNA expression levels, mRNA expression levels, serum cytokines, and leukocyte subsets. However, when the individual immunosenescence markers were grouped by pathways or functional terms, several shared biological functions were identified: antigen processing and presentation pathways, MAPK, mTOR, TCR, BCR, and calcium signaling pathways, as well as key cellular metabolic, proliferation and survival activities. Furthermore, the percent of CD4 and/or CD8 T cells lacking CD28 expression also correlated with miRNAs regulating clusters of genes known to be involved in viral infection. Integrated (DNA methylation, mRNA, miRNA, and protein levels) network biology analysis of immunosenescence-related pathways and genesets identified both known pathways (e.g., chemokine signaling, CTL, and NK cell activity), as well as a gene expression module not previously annotated with a known function. These results may improve our ability to predict immune responses to influenza and aid in new vaccine development, and highlight the need for additional studies to better define and characterize immunosenescence.
Keywords
- DNA methylation
- aging
- gene expression profiling
- immunity
- influenza A/H1N1 virus
- influenza vaccines
- miRNA
Multiple myeloma is an incurable plasma cell malignancy that is mostly restricted to the bone marrow. Cancer-induced dysfunction of cytotoxic T cells at the tumor site may be responsible for immune evasion and therapeutical failure of immunotherapies. Therefore, enhanced knowledge about the actual status of T cells in myeloma bone marrow is urgently needed. Here, we assessed the expression of inhibitory molecules PD-1, CTLA-4, 2B4, CD160, senescence marker CD57, and CD28 on T cells of naive and treated myeloma patients in the bone marrow and peripheral blood and collected data on T cell subset distribution in both compartments. In addition, T cell function concerning proliferation and expression of T-bet, IL-2, IFNγ, and CD107a was investigated after in vitro stimulation by CD3/CD28. Finally, data was compared to healthy, age-matched donor T cells from both compartments. Multicolor flow cytometry was utilized for the analyses of surface molecules, intracellular staining of cytokines was also performed by flow cytometry, and proliferation was assessed by H-thymidine incorporation. Statistical analyses were performed utilizing unpaired T test and Mann-Whitney U test. We observed enhanced T cell exhaustion and senescence especially at the tumor site. CD8 T cells expressed several molecules associated with T cell exhaustion (PD-1, CTLA-4, 2B4, CD160) and T cell senescence (CD57, lack of CD28). This phenotype was associated with lower proliferative capacity and impaired function. Despite a high expression of the transcription factor T-bet, CD8 T cells from the tumor site failed to produce IFNγ after CD3/CD28 in vitro restimulation and displayed a reduced ability to degranulate in response to T cell stimuli. Notably, the percentage of senescent CD57 CD28- CD8 T cells was significantly lower in treated myeloma patients when compared to untreated patients. T cells from the bone marrow of myeloma patients were more severely impaired than peripheral T cells. While our data suggest that terminally differentiated cells are preferentially deleted by therapy, immune-checkpoint molecules were still present on T cells supporting the potential of checkpoint inhibitors to reactivate T cells in myeloma patients in combination therapies. However, additional avenues to restore anti-myeloma T cell responses are urgently needed.
MeSH Terms
- Aged
- Blood Cells
- Bone Marrow Cells
- CD8-Positive T-Lymphocytes
- Case-Control Studies
- Cell Proliferation
- Cellular Senescence
- Female
- Humans
- Immunophenotyping
- Lymphocyte Activation
- Male
- Middle Aged
- Multiple Myeloma
- T-Lymphocyte Subsets
- T-Lymphocytes, Cytotoxic
Keywords
- Bone marrow
- Immune-checkpoint molecules
- Multiple myeloma
- T cell exhaustion
- T cell senescence
Corticosteroid resistance is a major barrier to effective treatment of COPD. We have shown that the resistance is associated with decreased expression of glucocorticoid receptor (GCR) by senescent CD28nullCD8 pro-inflammatory lymphocytes in peripheral blood of COPD patients. GCR must be bound to molecular chaperones heat shock proteins (Hsp) 70 and Hsp90 to acquire a high-affinity steroid binding conformation, and traffic to the nucleus. We hypothesized a loss of Hsp70/90 from these lymphocytes may further contribute to steroid resistance in COPD. Blood was collected from COPD (n = 10) and aged-matched controls (n = 10). To assess response to steroids, cytotoxic mediators, intracellular pro-inflammatory cytokines, CD28, GCR, Hsp70 and Hsp90 were determined in T and NKT-like cells in the presence of ± 10 μM prednisolone and 2.5 ng/mL cyclosporine A (binds to GCR-Hsp70/90 complex) using flow cytometry, western blot and fluorescence microscopy. A loss of expression of Hsp90 and GCR from CD28null CD8 T and NKT-like cells in COPD was noted (Hsp70 unchanged). Loss of Hsp90 expression correlated with the percentage of CD28null CD8 T and NKT-like cells producing IFNγ or TNFα in all subjects (eg, COPD: R = -0.763, p = 0.007 for T-cell IFNγ). Up-regulation of Hsp90 and associated decrease in pro-inflammatory cytokine production was found in CD28nullCD8 T and NKT-like cells in the presence of 10 μM prednisolone and 2.5 ng/mL cyclosporine A. Loss of Hsp90 from cytotoxic/pro-inflammatory CD28nullCD8 T and NKT-like cells could contribute to steroid resistance in COPD. Combination prednisolone and low-dose cyclosporine A therapy inhibits these pro-inflammatory cells and may reduce systemic inflammation in COPD.
MeSH Terms
- Adrenal Cortex Hormones
- Adult
- Anti-Inflammatory Agents
- CD28 Antigens
- Case-Control Studies
- Cyclosporine
- Cytokines
- Drug Resistance
- Drug Therapy, Combination
- HSP70 Heat-Shock Proteins
- HSP90 Heat-Shock Proteins
- Humans
- Killer Cells, Natural
- Middle Aged
- Phenotype
- Prednisolone
- Pulmonary Disease, Chronic Obstructive
- Receptors, Glucocorticoid
- T-Lymphocytes
Keywords
- CD28nullCD8 T and NKT-like cells
- COPD
- Hsp90
- IFNγ and TNFα
- Lymphocyte senescence
Age has been reported as an independent prognostic factor for melanoma-specific survival (MSS). We tested the hypothesis that age impacts the host anti-tumor immune response, accounting for age-specific survival outcomes in three unique melanoma patient cohorts. We queried the U.S. population-based Surveillance, Epidemiology, and End Results Program (SEER), the prospective tertiary care hospital-based Interdisciplinary Melanoma Cooperative Group (IMCG) biorepository, and the Cancer Genome Atlas (TCGA) biospecimen database to test the association of patient age at time of melanoma diagnosis with clinicopathologic features and survival outcomes. Age groups were defined as ≤45 (young), 46-65 (intermediate), and >65 (older). Each age group in the IMCG and TCGA cohorts was stratified by tumor infiltrating lymphocyte (TIL) measurements and tested for association with MSS. Differential expression of 594 immunoregulatory genes was assessed in a subset of primary melanomas in the IMCG and TCGA cohorts using an integrative pathway analysis. We analyzed 304, 476 (SEER), 1241 (IMCG), and 292 (TCGA) patients. Increasing age at melanoma diagnosis in both the SEER and IMCG cohorts demonstrated a positive correlation with tumor thickness, ulceration, stage, and mortality, however age in the TCGA cohort did not correlate with mortality. Older age was associated with shorter MSS in all three cohorts. When the young age group in both the IMCG and TCGA cohorts was stratified by TIL status, there were no differences in MSS. However, older IMCG patients with brisk TILs and intermediate aged TCGA patients with high lymphocyte scores (3-6) had improved MSS. Gene expression analysis revealed top pathways (T cell trafficking, communication, and differentiation) and top upstream regulators (CD3, CD28, IFNG, and STAT3) that significantly changed with age in 84 IMCG and 43 TCGA primary melanomas. Older age at time of melanoma diagnosis is associated with shorter MSS, however age's association with clinicopathologic features is dependent upon specific characteristics of the study population. TIL as a read-out of the host immune response may have greater prognostic impact in patients older than age 45. Recognition of age-related factors negatively impacting host immune responses may provide new insights into therapeutic strategies for the elderly.
MeSH Terms
- Aged
- Aging
- Cohort Studies
- Female
- Gene Expression Profiling
- Gene Expression Regulation, Neoplastic
- Humans
- Immunity
- Lymphocytes, Tumor-Infiltrating
- Male
- Melanoma
- Middle Aged
- Multivariate Analysis
- Neoplasm Staging
- Prognosis
- SEER Program
- Survival Analysis
Keywords
- Age
- Elderly
- Host immune response
- Melanoma
- SEER
- TCGA
- Tumor infiltrating lymphocytes
Melatonin plays a critical role in regulating photoperiodic signals and has recently been shown to decrease immunosenescence with age. In this study, we examined whether melatonin activates T lymphocytes as major adaptive immune cells in in vitro and in vivo models. Splenocytes, CD4( ), and naïve CD4 T lymphocytes were isolated from the spleen of BALB/c mice and the cell population patterns and mRNA profiles associated with T cell activation (CD28 and p21) and the melatonin receptor (MT1A and MT1B) were assessed. The T cell activation-related proteins Ki67 and Bcl2 were also evaluated to confirm the relationship between gene and protein levels. Our data clearly revealed that CD28, p21, MT1A, and MT1B mRNA were highly expressed in the presence of melatonin. Co-culture of CD4( ) T lymphocyte and peritoneal macrophage 7 days after melatonin administration to young and aged mice significantly increased APRIL mRNA, suggesting induction or maintenance of T lymphocyte responses. We also found that the intracellular amount of Ki67 and Bcl2 proteins were significantly upregulated in aged CD4( ) T lymphocytes, suggesting enhancing T cell proliferation and ling-term maintenance of memory T cells. Taken together, we conclude that melatonin supplementation may enhance immunity in aged individuals by upregulating immunosenescence indices in association with T lymphocytes and may be an attractive pharmacological candidate for aged and immunocompromised individuals.
Keywords
- CD4
- aging
- melatonin
- melatonin receptor
- naïve CD4
Natural killer (NK) cell receptors (NKRs) play a crucial role in the homeostasis of antigen-experienced T cells. Indeed, prolonged antigen stimulation may induce changes in the receptor repertoire of T cells to a profile that features NKRs. Chronic antigen exposure, at the same time, has been shown to trigger the loss of costimulatory CD28 molecules with recently reported intensified antigen thresholds of antigen-experienced CD8( ) T cells. In transplantation, NKRs have been shown to assist allograft rejection in a CD28-independent fashion. We discuss here a role for CD28-negative T cells that have acquired the competency of the NKR machinery, potentially promoting allorecognition either through T cell receptor (TCR) crossreactivity or independently from TCR recognition. Collectively, NKRs can bring about innate-like T cells by providing alternative costimulatory pathways that gain relevance in chronic inflammation, potentially leading to resistance to CD28-targeting immunosuppressants.
MeSH Terms
- Adaptive Immunity
- Aging
- Animals
- Antigens
- CD28 Antigens
- Gene Expression Regulation
- Humans
- Immunity, Innate
- Immunosuppression
- Inflammation
- Killer Cells, Natural
- Lymphocyte Activation
- Receptors, Antigen, T-Cell
- Receptors, Natural Killer Cell
- Signal Transduction
- T-Lymphocyte Subsets
Keywords
- NK cell receptors
- T cells
- adaptive immunity
- innate immunity
- transplantation
The role of alcohol consumption in HIV-related adaptive immune dysfunction is debated. We hypothesized that heavy drinking would be associated with greater evidence of immunosenescence (i.e., aging-related decline of adaptive immune function) among antiretroviral therapy (ART)-naïve HIV-infected individuals. Using data from the Russia ARCH cohort study, we conducted a cross-sectional analysis of ART-naïve HIV-infected individuals recruited between 2012 and 2014. Heavy drinking defined as >4 standard drinks in a day (or >14 standard drinks per week) for men and >3 per day (or >7 per week) for women, respectively. Percentage of CD8 and CD4 T-cells with a phenotype consistent with immunosenescence (i.e., expressing CD28- CD57 , or memory [CD45RO CD45RA ] phenotype and not the naïve [CD45RO- CD45RA ] phenotype). Multiple linear regression adjusted for confounders. Of 214 eligible participants, 61% were heavy drinkers. Mean age was 33 years and the cohort was predominantly male (72%). Hepatitis C prevalence was high (87%) and mean log10 HIV-1 RNA copies/ml was 4.6. We found no significant differences by drinking status in the percentage of immunosenescent, memory, or naïve CD8 or CD4 T-cells. In this cross-sectional analysis, heavy drinking in the setting of untreated HIV infection did not appear to be associated with alterations in T-cell phenotypes consistent with immunosenescence. To substantiate these findings, longitudinal studies should assess whether changes in alcohol consumption are associated with changes in these and other immunosenescent T-cell phenotypes.
MeSH Terms
- Adult
- Alcohol Drinking
- CD4-Positive T-Lymphocytes
- CD8-Positive T-Lymphocytes
- Cohort Studies
- Cross-Sectional Studies
- Female
- HIV Infections
- HIV-1
- Humans
- Immunosenescence
- Longitudinal Studies
- Male
- Phenotype
- Russia
- T-Lymphocyte Subsets
Keywords
- HIV
- Heavy Drinking
- Immunosenescence
- Russia
- T-Cell
Chronic systematic inflammation and reduced immune system fitness are considered potential contributing factors to the development of age-related frailty, but the underlying mechanisms are poorly defined. This exploratory study aimed to identify frailty-related inflammatory markers and immunological phenotypes in a cohort of community-dwelling adults aged ≥ 55 years. Frailty was assessed using two models, a Frailty Index and a categorical phenotype, and correlated with levels of circulating immune biomarkers and markers of senescence in immune cell subsets. We identified eight serological biomarkers that were associated with frailty, including sgp130, IL-2Rα, I-309, MCP-1, BCA-1, RANTES, leptin, and IL-6R. Frailty Index was inversely predicted by the frequency of CD3 , CD45RA , and central memory CD4 cells, and positively predicted by the loss of CD28 expression, especially in CD8 T cells, while frailty status was predicted by the frequency of terminal effector CD8 T cells. In γ/δ T cells, frailty was negatively associated with CD27, and positively associated with IFNγ TNFα- secretion by γ/δ2 cells and IFNγ-TNFα secretion by γ/δ2- cells. Increased numbers of exhausted and CD38 B cells, as well as CD14 CD16 inflammatory monocytes, were also identified as frailty-associated phenotypes. This pilot study supports an association between inflammation, cellular immunity, and the process of frailty. These findings have significance for the early identification of frailty using circulating biomarkers prior to clinical manifestations of severe functional decline in the elderly.
MeSH Terms
- Aged
- Aging
- Female
- Frail Elderly
- Frailty
- Humans
- Inflammation
- Longitudinal Studies
- Male
- Middle Aged
- Pilot Projects
- Singapore
Keywords
- B cells
- Gerotarget
- T cell subsets
- frailty risk
- immunosenescence
- inflammation
Oxidative damage and regular antigenic stimulation are main factors in accelerating immunosenescence. The present study was conducted to investigate new concepts of early immunosenescence in thalassaemia patients. Twenty seven beta-thalassaemia major patients and a group of matched healthy volunteers aged 10-30 years in Shahrekord, Iran were recruited into the study. Ferritin level was determined and CD4 or CD8 T cells were analysed versus phenotyping markers, CD27, CD28, CD57 and CCR7, by flowcytometry. Data were analysed by Mann-Whitney and Spearman's correlation coefficient test in SPSS 11.5. Absolute lymphocytosis and partial decrease in T cells were observed in the patients. CD4 CD57 and CD4 CCR7- T cells were significantly higher, whereas CD8 CD27 and CD8 CCR7 T cells were partially higher in patients. A negative correlation was observed between ferritin level and number of CD8 CD27 and CD8 CCR7 T cells, whereas the correlation was positive between ferritin level and number of CD57 T cells. Moderate alteration of T cell repertoire and increase in CCR27-, CCR7-, and CD57 T cells could reflect antigenic stimulation, decline in naïve T cells, and being closer to terminally differentiated cells. Effect of iron overload is potentially explained by positive correlation of blood transfusion and ferritin level with frequency of CD3 CD27- and that of ferritin with frequency of CD57 T cells.
Keywords
- Autosomal disorder
- Immunosenescence
- Oxidative damage
Aging is a major risk factor for several conditions including neurodegenerative, cardiovascular diseases and cancer. Functional impairments in cellular pathways controlling genomic stability, and immune control have been identified. Biomarker of immune senescence is needed to improve vaccine response and to develop therapy to improve immune control. To identify phenotypic signature of circulating immune cells with aging, we enrolled 1068 Chinese healthy volunteers ranging from 18 to 80 years old. The decreased naïve CD4 and CD8 T cells, increased memory CD4 or CD8 T cells, loss of CD28 expression on T cells and reverse trend of CD38 and HLA-DR, were significant for aging of immune system. Conversely, the absolute counts and percentage of NK cells and CD19 B cells maintained stable in aging individuals. The Chinese reference ranges of absolute counts and percentage of peripheral lymphocyte in this study might be useful for future clinical evaluation.
MeSH Terms
- Adolescent
- Adult
- Aged
- Aged, 80 and over
- Aging
- B-Lymphocytes
- Female
- Healthy Volunteers
- Humans
- Killer Cells, Natural
- Lymphocyte Activation
- Lymphocyte Count
- Lymphocyte Subsets
- Male
- Middle Aged
- Reference Values
- Young Adult
Keywords
- aging
- flow cytometry
- lymphocyte subsets
- reference range
Psychosocial stress is thought to play a key role in the acceleration of immunological aging. This study investigated the relationship between lifetime and past-year history of post-traumatic stress disorder (PTSD) and the distribution of T cell phenotypes thought to be characteristic of immunological aging. Data were from 85 individuals who participated in the community-based Detroit Neighborhood Health Study. Immune markers assessed included the CD4:CD8 ratio, the ratio of late-differentiated effector (CCR7-CD45RA CD27-CD28-) to naïve (CCR7 CD45RA CD27 CD28 ) T cells, the percentage of KLRG1-expressing cells, and the percentage of CD57-expressing cells. In models adjusted for age, gender, race/ethnicity, education, smoking status, and medication use, we found that past-year PTSD was associated with statistically significant differences in the CD8 T cell population, including a higher ratio of late-differentiated effector to naïve T cells, a higher percentage of KLRG1 cells, and a higher percentage of CD57 cells. The percentage of CD57 cells in the CD4 subset was also significantly higher and the CD4:CD8 ratio significantly lower among individuals who had experienced past-year PTSD. Lifetime PTSD was also associated with differences in several parameters of immune aging. PTSD is associated with an aged immune phenotype and should be evaluated as a potential catalyzer of accelerated immunological aging in future studies.
MeSH Terms
- Adult
- Aged
- Aged, 80 and over
- Cellular Senescence
- Female
- Humans
- Immunophenotyping
- Male
- Middle Aged
- Phenotype
- Stress Disorders, Post-Traumatic
- T-Lymphocyte Subsets
- Young Adult
Keywords
- Aging
- Detroit
- Immunity
- Immunosenescence
- Post traumatic stress disorder
- T cells
A latent infection with cytomegalovirus (CMV), a ubiquitous beta herpesvirus, is associated with an accumulation of late-differentiated memory T-cells, often accompanied by a reciprocal reduced frequency of early-differentiated cells (commonly also referred to as "naïve"). However, this impact of CMV on T-cell phenotypes is variable between individuals. Our previous findings in a subgroup of participants in the Leiden familial Longevity Study indicated an important role of genetics. For further testing, we have analyzed middle-aged monozygotic (MZ, n = 42) and dizygotic (DZ, n = 39) twin pairs from the Danish Twin Registry for their T-cell differentiation status, assessed by surface expression of CD27, CD28, CD57, and KLRG-1. We observed a significant intraclass correlation between cotwins of MZ, but not DZ pairs for the differentiation status of CD4 and CD8 subsets. Classical heritability analysis confirmed a substantial contribution of genetics to the differentiation status of T-cells in CMV infection. The humoral (IgG) response to different CMV antigens also seems to be genetically influenced, suggesting that a similar degree of immune control of the virus in MZ twins might be responsible for their similar T-cell differentiation status. Thus, the way T-cells differentiate in the face of a latent CMV infection, and the parallel humoral responses, both controlling the virus, are genetically influenced.
MeSH Terms
- Aged
- Aged, 80 and over
- Aging
- CD4-Positive T-Lymphocytes
- Cell Differentiation
- Cytomegalovirus Infections
- Denmark
- Female
- Flow Cytometry
- Humans
- Immunity, Humoral
- Immunoblotting
- Immunoglobulin G
- Longevity
- Longitudinal Studies
- Male
- Phenotype
Keywords
- Genetics
- Heritability
- Humoral responses
- Twins
Shifts in CD8 T-cell subsets that are hallmarks of immunosenescence are observed in ageing and in conditions of chronic immune stimulation. Presently, there is limited documentation of such changes in lung cancer and other malignancies affecting the lungs. Changes in CD8 T-cell subsets, based on the expression of CD28 and CD57, were analysed in patients with various forms of cancer affecting the lungs, undergoing chemotherapy and in a control group over six months, using multi-colour flow cytometry. The differences between patients and controls, and the changes in the frequency of CD8 T-cell subpopulations among lung cancer patients corresponded to those seen in immunosenescence: lower CD8-/CD8 ratio, lower proportions of CD28 CD57- cells consisting of naïve and central memory cells, and higher proportions of senescent-enriched CD28-CD57 cells among the lung cancer patients, with the stage IV lung cancer patients showing the most pronounced changes. Also observed was a tendency of chemotherapy to induce the formation of CD28 CD57 cells, which, in line with the capacity of chemotherapy to induce the formation of senescent cells, might provide more evidence supporting CD28 CD57 cells as senescent cells. Immunosenescence was present before the start of the treatment; it appeared to be pronounced in patients with advanced cases of malignancies affecting the lungs, and might not be averted by chemotherapy.
MeSH Terms
- Aged
- Antineoplastic Agents
- CD28 Antigens
- CD57 Antigens
- CD8-Positive T-Lymphocytes
- Case-Control Studies
- Cellular Senescence
- Female
- Flow Cytometry
- Humans
- Immunosenescence
- Lung Neoplasms
- Male
- Middle Aged
- T-Lymphocyte Subsets
There are well-known alterations occurring within the immune system with aging. Collectively, these changes are known as immunosenescence. The incidence of malignancies also increases with age. The aim of this study was to determine the presence of immunosenescence biomarkers in non-small cell lung cancer (NSCLC) patients and to evaluate some of them as predictive biomarkers of CIMAvax-EGF cancer vaccine efficacy. Sixty-six NSCLC patients, vaccinated or not with CIMAvax-EGF cancer vaccine, and 37 age-matched controls were enrolled. Peripheral blood samples were studied for CD19 , CD4 , CD8 , CD28-, CD57 and CD45RA subpopulations by flow cytometry. Absolute count of CD19 and the CD4/CD8 ratio were significantly lower in NSCLC patients than in age-paired controls, while highly differentiated T cells increased in NSCLC patients treated with platinum-based chemotherapy. Using Cox regression, we were able to dichotomize the patient population according to biomarkers. Vaccinated patients with frequency <24 % of CD8 CD28- T cells, >40 % of CD4 T cells and CD4/CD8 ratio higher than two at the beginning of immunotherapy achieved a 20-month increase in median survival regarding control patients. Distribution of lymphocyte subsets was influenced by cancer and chemotherapy in NSCLC patients. CD19 B cells decrease by cancer disease and not by chemotherapy, and CD28- subpopulations increase by chemotherapy and not by cancer. The proportion of CD8 CD28- T cells, CD4 T cells and CD4/CD8 ratio can be used as predictive biomarkers of CIMAvax-EGF efficacy in NSCLC patients and thereby could, be a useful tool for a personalized treatment.
MeSH Terms
- Biomarkers
- Female
- Humans
- Immunosenescence
- Lung Neoplasms
- Male
- Survival Analysis
Keywords
- Cancer vaccine
- Immunosenescence
- Immunosenescence markers
- Non-small cell lung cancer
Patients with glioblastoma multiforme (GBM) are immunosuppressed and have a broad range of immunological defects in both innate and adaptive immune responses. GBMs are frequently infected with human cytomegalovirus (HCMV), a virus capable of causing immunosuppression. In 42 HCMV-positive GBM patients in a clinical trial (VIGAS), we investigated T-cell phenotypes in the blood and assessed their relation to survival. Blood was collected before and 3, 12, and 24 weeks after surgery, and the frequency of T-cell subsets was compared with that in 26 age-matched healthy controls. GBM patients had lower levels of CD3 cells than the controls, but had significantly higher levels of CD4 CD28 T cells before and 3 and 12 weeks after surgery and increased levels of CD4 CD57 and CD4 CD57 CD28 T cells at all-time points. These T-cell subsets were associated with both immunosenescence and HCMV infection. GBM patients also had higher levels of γδ T cells at all-times after surgery and lower levels of CD4 CD25 cells before and 3 weeks after surgery than healthy controls. Overall survival was significantly shorter in patients with higher levels of CD4 CD28 T cells ([i]p =[/i] 0.025), CD4 CD57 T ([i]p =[/i] 0.025) cells, and CD4 CD28 CD57 CD28 T cells ([i]p <[/i] 0.0004) at 3 weeks after surgery. Our findings indicate that signs of immunosenescence in the CD4 compartment are associated with poor prognosis in patients with HCMV-positive GBMs and may reflect the HCMV activity in their tumors.
Keywords
- T cells
- cytomegalovirus
- glioblastoma
- immunosenescence
- survival
During organismal aging, human T-cells shift towards less functional phenotypes, often called senescent cells. As these cells have not been well characterized, we aimed to relate surface markers of human T-cell senescence with characteristics of in vitro cellular aging and to further characterize these cells. We identified, by flow cytometry, subpopulations of CD8 T-cells based on CD57 and CD28 expression, and tested them for some markers of cellular senescence, apoptosis, differentiation and homing. Elderly persons presented significantly higher proportions not only of CD28-CD57 , but also of CD28 CD57 cells. CD28 CD57 cells had the highest expression of p16, p21, Bcl-2, CD95, CD45RO, CCR5 and PD-1, thereby arguing in favor of a senescent phenotype. Among CD8 T-lymphocytes, CD28 CD57 cells represent a subset with some senescent features that are distinct from the CD28-CD57 cells.
MeSH Terms
- Aged
- Aging
- Biomarkers
- CD28 Antigens
- CD57 Antigens
- CD8-Positive T-Lymphocytes
- Cell Differentiation
- Cellular Senescence
- Cyclin-Dependent Kinase Inhibitor p16
- Cyclin-Dependent Kinase Inhibitor p21
- Flow Cytometry
- Humans
- Immunophenotyping
- Phenotype
Keywords
- CD28
- CD57
- CXCR2
- Cellular aging
- p16
- p21
The chronic inflammatory environment associated with systemic lupus erythematosus can lead to an accelerated immunosenescence responsible for the endothelial damage and increased cardiovascular risk observed in these patients. The present study analyzed two populations with opposite effects on vascular endothelium, angiogenic T cells and the senescent CD4( )CD28(null) subset, in 84 systemic lupus erythematosus patients and 46 healthy controls. Also, 48 rheumatoid arthritis patients and 72 individuals with traditional cardiovascular risk factors participated as disease controls. Phenotypic characterization of CD28( ) and CD28(null) cells was performed by analyzing markers of senescence (CCR7, CD27, CD57) and cytotoxicity (CD56, perforin, granzyme B, IFN-γ). IL-1β, IL-6, IL-8, IL-10, IL-12, IL-17A, IFN-α, IFN-γ, TNF-α, B lymphocyte stimulator, and GM-CSF serum levels were analyzed in systemic lupus erythematosus patients and healthy controls. CD4( )CD28(null) cells were notably increased in the systemic lupus erythematosus patients and disease controls compared with healthy controls. In contrast, angiogenic T cells were only reduced in the disease controls (those with rheumatoid arthritis or traditional cardiovascular risk factors). Nevertheless, an anomalous presence of CD28(null)-angiogenic T cells, with cytotoxic and senescent characteristics, was noted in systemic lupus erythematosus patients in association with anti-dsDNA titer, anti-SSA/Ro antibodies and circulating TNF-α, IL-8, IFN-α, and B lymphocyte stimulator amounts. This subset was also detected in those with traditional cardiovascular risk factors but not in the rheumatoid arthritis patients. In contrast, CD28( )-angiogenic T cells were reduced in the systemic lupus erythematosus patients with cardiovascular disorders. In conclusion, CD28 expression must be used to redefine the angiogenic T cell population, because in pathologic conditions, a senescent CD28(null)-angiogenic T cell subset with inflammatory, rather than protective, effects could be present.
MeSH Terms
- Adult
- Aged
- CD28 Antigens
- Cytokines
- Female
- Humans
- Immunosenescence
- Lupus Erythematosus, Systemic
- Male
- Middle Aged
- T-Lymphocyte Subsets
Keywords
- BLyS
- CD4 CD28null
- IFN-α
- Tang cells
- cardiovascular disease
Both aging and obesity are related to dysregulated immune function, which may be responsible for increased risk of infection and also chronic non-infectious diseases. Dietary lipids have been shown to impact immune and inflammatory responses and cardio-metabolic risk factors. No information on the impact of olive oil on immune responses of overweight and obese older adults is available. We aimed to determine the effect of replacing oils used in a typical American diet with extra virgin olive oil for 3 months on immune responses and cardio-metabolic risk factors in overweight and obese older adults. This was a randomized, single-blinded and placebo-controlled trial in 41 overweight or obese participants (aged ≥ 65) who consumed a typical American diet. Participants in the control (CON, n = 21) group were provided with a mixture of corn, soybean oil and butter, and those in the olive oil (OO, n = 20) group, with extra virgin olive oil, to replace substitutable oils in their diet. At baseline and 3 months, we measured blood pressure, biochemical and immunological parameters using fasting blood, and delayed-type hypersensitivity (DTH) skin response. Compared to the CON group, the OO group showed decreased systolic blood pressure (P < 0.05), a strong trend toward increased plasma HDL-C concentrations (P = 0.06), and increased anti-CD3/anti-CD28 -stimulated T cell proliferation (P < 0.05). No differences were found in T cell phenotype, cytokine production, and DTH response between the two groups. Our results indicate that substitution of oils used in a typical American diet with extra virgin olive oil in overweight and obese older adults may have cardio-metabolic and immunological health benefits. This trial was registered at clinicaltrials.gov as NCT01903304.
Keywords
- Aging
- Cardio-metabolic
- Immune response
- Obesity
- Olive oil
HIV-infected individuals suffer from accelerated immunologic aging. One of the most prominent changes during T lymphocyte aging is the accumulation of CD28(null) T lymphocytes, mainly CD8( ) but also CD4( ) T lymphocytes. Enhancing the functional properties of these cells may be important because they provide antigen-specific defense against chronic infections. The objective of this study was to compare the responses of CD4( )CD28(null) and CD8( )CD28(null) T lymphocytes from HIV-infected patients to the immunomodulatory effects of cytokines IL-15 and IL-21. We quantified the frequencies of CD4( )CD28(null) and CD8( )CD28(null) T lymphocytes in peripheral blood from 110 consecutive, HIV-infected patients and 25 healthy controls. Patients showed increased frequencies of CD4( )CD28(null) and CD8( )CD28(null). Both subsets were positively correlated to each other and showed an inverse correlation with the absolute counts of CD4( ) T lymphocytes. Higher frequencies of HIV-specific and CMV-specific cells were found in CD28(null) than in CD28( ) T lymphocytes. Activation of STAT5 by IL-15 and STAT3 by IL-21 was higher in CD28(null) compared with CD28( ) T lymphocytes. Proliferation, expression of CD69, and IFN-γ production in CD28(null) T lymphocytes were increased after treatment with IL-15, and IL-21 potentiated most of those effects. Nevertheless, IL-21 alone reduced IFN-γ production in response to anti-CD3 stimulation but increased CD28 expression, even counteracting the inhibitory effect of IL-15. Intracytoplasmic stores of granzyme B and perforin were increased by IL-15, whereas IL-21 and simultaneous treatment with the 2 cytokines also significantly enhanced degranulation in CD4( )CD28(null) and CD8( )CD28(null) T lymphocytes. IL-15 and IL-21 could have a role in enhancing the effector response of CD28(null) T lymphocytes against their specific chronic antigens in HIV-infected patients.
MeSH Terms
- Adult
- Antigens, CD
- Antigens, Differentiation, T-Lymphocyte
- CD28 Antigens
- CD4-Positive T-Lymphocytes
- CD8-Positive T-Lymphocytes
- Cell Degranulation
- Cell Proliferation
- Cohort Studies
- Demography
- Female
- Granzymes
- HIV Antigens
- HIV Infections
- Humans
- Interferon-gamma
- Interleukin-15
- Interleukins
- Lectins, C-Type
- Male
- Middle Aged
- Perforin
- STAT3 Transcription Factor
- STAT5 Transcription Factor
- Tumor Suppressor Proteins
- Up-Regulation
- Young Adult
Keywords
- T lymphocyte differentiation
- cytotoxicity
- immunosenescence
In multicellular organisms the proper system functionality is ensured by the balance between cell division, differentiation, senescence and death. This balance is changed during aging. Immunosenescence plays a crucial role in aging and leads to the shrinkage of T cell repertoire and the propensity to apoptosis. The elimination of expanded T cells at the end of immune response is crucial to maintain homeostasis and avoid any uncontrolled inflammation. Resting mature T lymphocytes, when activated via their antigen-specific receptor (TCR) and CD28 co-receptor, start to proliferate and then undergo the so called activation induced cell death (AICD), which mechanistically is triggered by the death receptor and leads to apoptosis. T lymphocytes, like other cells, are also exposed to damage, which can trigger the so called damage-induced cell death (DICD). It was hypothesized that oxidative stress and chronic antigenic load increasing with age reduced lymphocyte susceptibility to DICD and enhanced a proinflamatory status leading to increased AICD. However, data collected so far are inconsistent and does not support this assumption. Systematic and comprehensive studies are still needed for conclusive elucidation of the role of AICD and DICD in human immunosenescence, including the role of autophagy and necroptosis in the processes.
MeSH Terms
- Aging
- Apoptosis
- Cellular Senescence
- Humans
- Lymphocyte Activation
- Oxidative Stress
- Receptors, Antigen, T-Cell
Keywords
- Apoptosis
- Autophagy
- DNA damage
- Immunosenescence
- Inflammaging
- Lymphocytes
- Necroptosis
Although influenza causes significant morbidity and mortality in the elderly, the factors underlying the reduced vaccine immunogenicity and efficacy in this age group are not completely understood. Age and immunosenescence factors, and their impact on humoral immunity after influenza vaccination, are of growing interest for the development of better vaccines for the elderly. We assessed associations between age and immunosenescence markers (T cell receptor rearrangement excision circles - TREC content, peripheral white blood cell telomerase - TERT expression and CD28 expression on T cells) and influenza A/H1N1 vaccine-induced measures of humoral immunity in 106 older subjects at baseline and three timepoints post-vaccination. TERT activity (TERT mRNA expression) was significantly positively correlated with the observed increase in the influenza-specific memory B cell ELISPOT response at Day 28 compared to baseline (p-value=0.025). TREC levels were positively correlated with the baseline and early (Day 3) influenza A/H1N1-specific memory B cell ELISPOT response (p-value=0.042 and p-value=0.035, respectively). The expression and/or expression change of CD28 on CD4 and/or CD8 T cells at baseline and Day 3 was positively correlated with the influenza A/H1N1-specific memory B cell ELISPOT response at baseline, Day 28 and Day 75 post-vaccination. In a multivariable analysis, the peak antibody response (HAI and/or VNA at Day 28) was negatively associated with age, the percentage of CD8 CD28 low T cells, IgD CD27- naïve B cells, and percentage overall CD20- B cells and plasmablasts, measured at Day 3 post-vaccination. The early change in influenza-specific memory B cell ELISPOT response was positively correlated with the observed increase in influenza A/H1N1-specific HAI antibodies at Day 28 and Day 75 relative to baseline (p-value=0.007 and p-value=0.005, respectively). Our data suggest that influenza-specific humoral immunity is significantly influenced by age, and that specific markers of immunosenescence (e.g., the baseline/early expression of CD28 on CD4 and/or CD8 T cells and T cell immune abnormalities) are correlated with different humoral immune response outcomes observed after vaccination in older individuals, and thus can be potentially used to predict vaccine immunogenicity.
MeSH Terms
- Age Factors
- Aged
- Aged, 80 and over
- B-Lymphocytes
- Female
- Humans
- Immunity, Humoral
- Immunosenescence
- Influenza A Virus, H1N1 Subtype
- Influenza Vaccines
- Influenza, Human
- Male
- Middle Aged
- T-Lymphocytes
- Telomerase
- Time Factors
- Vaccination
Changes in sub-populations of cytotoxic (CD8 ) T-cells, which are observed in aging and in conditions of chronic immune stimulation, are not well-documented in cancer. Using flow cytometry, CD8 T-cell subsets were analyzed in patients with breast cancer undergoing DNA-damaging chemotherapy and in an older female control group during a six-month longitudinal study, to explore shifts in CD8 T-cells and the effect of DNA-damaging chemotherapy on different T-cell sub-populations. As expected, there was a consistent decrease in absolute numbers of leukocytes, lymphocytes, T-cells and CD8 T-cells during chemotherapy in patients with cancer. Among the T-cells, there was a lower CD8-/CD8 ratio, persisting over the six months, in patients with cancer compared to controls. The proportion of CD28-CD57 cells also remained higher among patients with cancer throughout the sampling duration. The number of CD28 CD57- and CD28-CD5- cells decreased faster during DNA-damaging chemotherapy than CD28 CD57 and CD28-CD57 cells, while only CD28-CD57- cells showed a significant reconstitutive capacity after six months. Immunosenescence appeared to be pronounced in patients with breast cancer, with senescent CD8 T-cells playing a role. The normal condition was not restored after six months of chemotherapy.
MeSH Terms
- Adult
- Aged
- Breast Neoplasms
- CD28 Antigens
- CD57 Antigens
- CD8-Positive T-Lymphocytes
- Cellular Senescence
- DNA Damage
- Female
- Humans
- Middle Aged
Keywords
- CD28
- CD57
- breast cancer
- cellular senescence
- chemotherapy
- immunosenescence
Hepatitis C virus (HCV) causes persistent disease in ~85% of infected individuals, where the viral replication appears to be tightly controlled by HCV-specific CD8 T cells. Accumulation of senescent T cells during infection results in considerable loss of functional HCV-specific immune responses. We characterized the distinct T-cell phenotypes based on the expression of costimulatory molecules CD28 and CD27, senescence markers PD-1 and CD57, chronic immune activation markers CD38 and HLA-DR, and survival marker CD127 (IL-7R) by flow cytometry following activation of T cells using HCV peptides and phytohemagglutinin. HCV-specific CD4 and CD8 T cells from chronic HCV (CHC) patients showed increased expression of PD-1. Furthermore, virus-specific CD4 T cells of CHC-infected subjects displayed relatively increased expression of HLA-DR and CD38 relative to HCV-specific CD8 T cells. The CD4 and CD8 T cells from HCV-infected individuals showed significant increase of late-differentiated T cells suggestive of immunosenescence. In addition, we found that the plasma viral loads positively correlated with the levels of CD57 and PD-1 expressed on T cells. Chronic HCV infection results in increased turnover of late-senescent T cells that lack survival potentials, possibly contributing to viral persistence. Our findings challenge the prominence of senescent T-cell phenotypes in clinical hepatitis C infection.
MeSH Terms
- ADP-ribosyl Cyclase 1
- Adult
- CD28 Antigens
- CD4-Positive T-Lymphocytes
- CD57 Antigens
- CD8-Positive T-Lymphocytes
- Case-Control Studies
- Cellular Senescence
- Female
- Flow Cytometry
- HLA-DR Antigens
- Hepatitis C, Chronic
- Humans
- Interleukin-7 Receptor alpha Subunit
- Lymphocyte Activation
- Male
- Middle Aged
- Programmed Cell Death 1 Receptor
- T-Lymphocytes
- Tumor Necrosis Factor Receptor Superfamily, Member 7
- Young Adult
Keywords
- CD38
- CD57
- HCV infection
- IL-7R
- PD-1
- immunosenescence
This double-blind, placebo-controlled clinical trial was conducted to test whether Lactobacillus gasseri TMC0356 (TMC0356) can modify the immune response in the elderly. Heat-killed TMC0356 or placebo was orally administered to 28 healthy subjects aged 50-70 years old for 4 weeks at a dosage of 1.0×10(9) cfu/day. Peripheral blood mononuclear cells (PBMCs) were collected from the subjects before and after the study completion, together with general health and blood examination records. Isolated PBMCs were examined for the number of T cells, CD8( )CD28( ) cells, native T cells, B cells, natural killer (NK) cells and the ratios of CD4/CD8 T cells and native/memory T cells. NK cell activation and concanavalin A-induced lymphocyte transformation of the isolated PBMCs were also examined. The number of CD8( ) T cells significantly increased in the subjects after TMC0356 oral administration (P<0.05). Furthermore, the population of CD8( )CD28( ) T cells and the amount of lymphocyte transformation both significantly decreased in PBMCs from the placebo group (P<0.05). However, such changes were not observed in the subjects exposed to TMC0356. These results suggest that TMC0356 can increase the number of CD8( ) T cells and reduce CD28 expression loss in CD8( ) T cells of the elderly. The effect of TMC0356 on immune responses in the elderly may enhance their natural defence mechanisms against pathogenic infections.
MeSH Terms
- Administration, Oral
- Aged
- Cell Differentiation
- Cell Proliferation
- Concanavalin A
- Double-Blind Method
- Hot Temperature
- Humans
- Immunologic Factors
- Lactobacillus
- Leukocyte Count
- Leukocytes, Mononuclear
- Male
- Microbial Viability
- Middle Aged
- Placebos
- Probiotics
- Treatment Outcome
Keywords
- CD8 CD28 T cells
- Lactobacillus gasseri TMC0356
- immunosenescence
- probiotics
Given the protective roles of 25-hydroxyvitamin D (25[OH]D or vitamin D) in musculoskeletal health and the potential beneficial effects of vitamin D supplementation in reducing the risk of various chronic diseases, intensive repletion of vitamin D has been widely advocated. Of note, CD8 T cells have the highest levels of the vitamin D receptor compared with other major immune cells. The effects of vitamin D on CD8 T cells during aging, however, remain unclear. This study determined the relationship between vitamin D levels and CD8 T-cell status in 34 healthy female subjects (all >60 years old). The CD8 T cell phenotype was defined by the surface expression of CD28 and CD95. The low-25(OH)D serum groups (≤30 ng/ml) had higher percentages of CD28 CD95 CD8 (naïve) T cells and lower percentages of CD28 CD95 CD8 (effector) T cells. By contrast, subjects with high levels of 25(OH)D had very low percentages of naïve CD8 T cells but very high percentages of effector CD8 T cells. There was a significant inverse correlation between 25(OH)D levels and the frequency of naïve CD8 T cells. The results show that higher levels of vitamin D are correlated with decreased frequencies of naïve CD8 T cells during early aging, suggesting that higher levels of 25(OH)D accelerate CD8 T-cell senescence. These results warrant the further evaluation of the effects of vitamin D supplementation in immune aging.
Keywords
- human
- immunosenescence
- naïve CD8
- vitamin D
Low CD4/CD8 T-cell ratios occur in conditions associated with reduced immune resilience, including older age and HIV infection. Effective antiretroviral therapy increases CD4/CD8 T-cell ratios, but often not to preinfection levels. The reasons for this deficit remain unclear. As cytomegalovirus (CMV) infection exacerbates falling CD4/CD8 T-cell ratios and immune senescence in the old elderly population, we investigated whether CMV infection is associated with refractory inversion of CD4/CD8 T-cell ratios and increased phenotypic evidence of immune senescence in HIV infection. An observational cohort study of HIV-infected individuals attending the Newfoundland and Labrador Provincial HIV Clinic in St. John's. CMV infection status was determined by ELISA with infected cell lysate. Expression of CD28 and CD57 on CD8 T cells and cellular immune responses against CMV were measured by flow cytometry. We compared CD4/CD8 T-cell ratios, percentage of CD8 T cells expressing CD28 and percentage of CD8 T cells expressing CD57 between groups of HIV-infected persons discordant for CMV infection. The CMV-seronegative group had significantly higher CD4/CD8 T-cell ratios, more frequent normalization of the ratio to at least 1, and lesser phenotypic evidence of immune senescence. CMV infection is associated with reduced immune reconstitution in HIV infection, even with suppression of HIV replication below detectable levels. This suggests that CMV infection, or some related factor, influences immune resilience in the setting of HIV infection.
MeSH Terms
- AIDS-Related Opportunistic Infections
- Adult
- Aging
- Antiretroviral Therapy, Highly Active
- CD4-CD8 Ratio
- Cohort Studies
- Cytomegalovirus
- Cytomegalovirus Infections
- Female
- HIV Infections
- Humans
- Immunologic Memory
- Male
- Middle Aged
- Phenotype
The human immune system undergoes age-related changes that can lead to increased disease susceptibility. Using the baboon as a model for human immune system aging, we examined age-related changes in relative and absolute numbers of T cell subpopulations, cytomegalovirus (CMV) titer and markers of inflammation. In addition, the effect of gender, social status and peer group on lymphocyte subpopulations was determined. Relative and absolute numbers of total lymphocytes (CD3 ), T helper cells (CD4 ), and cytotoxic T cells (CD8 ) increased with age. The proportion of naïve T cells (CD45RA ) decreased, while the total number of cells negative for the co-stimulatory receptor, CD28 (CD28-) increased in an age-dependent manner. Furthermore, CMV titers were negatively correlated with the number of naive CD4 cells. IL-6 and cortisol concentration were also negatively associated with T cell subpopulations. Additionally, socially dominant baboons exhibited decreases in naïve CD4 and CD8 cells (by 65% and 52%, respectively) compared to subordinate animals. These results suggest that factors such as CMV exposure and inflammation may contribute to the age-related decline in immune health and indicate that factors like social status should be considered when studying immunosenescence in animal models.
MeSH Terms
- Age Factors
- Aging
- Animals
- Biomarkers
- CD4-Positive T-Lymphocytes
- CD8-Positive T-Lymphocytes
- Cytomegalovirus
- Cytomegalovirus Infections
- Hydrocortisone
- Immune System
- Inflammation
- Interleukin-6
- Papio
- T-Lymphocyte Subsets
Aging is associated with an increased susceptibility to infections and diseases. It has also been associated with reduced functionality and altered distribution of immune cells, especially T cells. Whereas classical α/β T cells, especially CD8( ) T cells, were shown to be highly susceptible to aging, the effects of viral persistent stimulations on the fate of γ/δ T cells are much less documented. Healthy, elderly individuals of Chinese ethnical background were recruited under the aegis of SLAS-II. In this observational study, γ/δ T cell populations were characterized by flow cytometry and compared with the α/β CD4( ) and CD8( ) T cells in elderly and young controls. In our study, we identified a reduced frequency of γ/δ T cells but not α/β T cells with aging. The classical markers of α/β T cell aging, including CD28, CD27, and CD57, did not prove significant for γ/δ T cells. The extreme range of expression of these markers in γ/δ T cells was responsible for the lack of relationship between γ/δ T cell subsets, CD4/CD8 ratio, and anti-CMV titers that was significant for α/β T cells and, especially, CD8( ) T cells. Although markers of aging for γ/δ T cells are not clearly identified, our data collectively suggest that the presence of CD27 γ/δ T cells is associated with markers of α/β T cell aging.
MeSH Terms
- Aged
- Aging
- Antigens, Surface
- Biomarkers
- Cellular Senescence
- Female
- Humans
- Immunophenotyping
- Lymphocyte Count
- Male
- Middle Aged
- Receptors, Antigen, T-Cell, alpha-beta
- Receptors, Antigen, T-Cell, gamma-delta
- T-Lymphocyte Subsets
Keywords
- CD4/CD8 ratio
- cell differentiation
- cellular markers
- immunosenescence
- penotyping
- persistent infections
Studies indicated significantly decreased expression of interleukin-2 (IL-2) with age. This decrease could be a major contributory factor to the increased frequency of morbidity and mortality among the elderly. C-rel is a key coregulator of IL-2 expression. However, it is unknown whether aging inhibits normal c-rel activation, thereby decreasing production of IL-2. We analyzed the dynamics of IL-2 expression in CD4( )T cells from different aged rats (young group: around 6 months (n=6), aged group: around 24 months (n=6)). The expression of the CD3 receptor and CD28 receptor in the CD4( )T cells was assessed by flow cytometry. Translocation of c-rel and its protein level in the cytoplasm and nucleus at different time points were detected by confocal microscopy and Western blotting. Chromatin immunoprecipitation (ChIP) was used to analyze the status of c-rel binding to the IL-2 promoter region in the different aged rats. Our results showed the CD4( )T cells from young rats and aged rats showed different expression kinetics of IL-2 after stimulation. The expression level of IL-2 was higher in young rats compared with aged rats at 24h and 48h. Data showed lower CD3 receptor expression on CD4( )T cells from aged rats compared with young rats. Although the CD28 receptors declined on the aged CD4( )T cells, the difference was not significant. After stimulation for 0.5h, more c-rel was translocated into nucleus markedly compared with that in the aged group. ChIP showed that in aged CD4( )T cells, c-rel DNA binding was inhabited compared with that in young cells. Therefore, reduced IL-2 production in activated CD4( )T cells from aged rats is associated with concomitant impairments in the activation of c-rel.
MeSH Terms
- Active Transport, Cell Nucleus
- Age Factors
- Aging
- Animals
- Blotting, Western
- CD28 Antigens
- CD3 Complex
- CD4-Positive T-Lymphocytes
- Cell Nucleus
- Flow Cytometry
- Gene Expression
- Interleukin-2
- Male
- Microscopy, Confocal
- Promoter Regions, Genetic
- Protein Binding
- Proto-Oncogene Proteins c-rel
- Rats
- Rats, Sprague-Dawley
- Reverse Transcriptase Polymerase Chain Reaction
Keywords
- Aging
- C-rel
- Immunosenescence
- Interleukin-2
- Transcription
Unlike cytomegalovirus (CMV) infection and aging, human immunodeficiency virus (HIV) decreases the proportion of CD28(-)CD8( ) T cells expressing CD57. Whether this abnormality predicts mortality in treated HIV infection and can be reversed by early antiretroviral therapy (ART) remains unknown. We sampled recently HIV-infected individuals (<6 months) and HIV-uninfected controls and compared longitudinal changes in the proportion of CD28(-)CD8( ) T cells expressing CD57 between those who initiated ART early (<6 months) vs later (≥2 years). We also assessed the relationship between this phenotype and mortality in a nested case-control study of ART-suppressed chronically infected individuals. Compared to HIV-uninfected controls (n = 15), individuals who were recently infected with HIV had lower proportions of CD28(-)CD8( ) T cells expressing CD57 (P < .001), and these proportions increased during ART. The early ART group (n = 33) achieved normal levels, whereas the later ART group (n = 30) continued to have lower levels than HIV-uninfected controls (P = .02). Among 141 ART-suppressed participants in the SOCA study, those in the lowest quartile of CD28(-)CD8( ) T cells expressing CD57 had 5-fold higher odds of mortality than those in the highest quartile (95% CI, 1.6-15.9, P = .007). Abnormally low proportions of CD28(-)CD8( ) T cells expressing CD57 predict increased mortality during treated HIV infection and may be reversed with early ART initiation.
MeSH Terms
- Adult
- Anti-HIV Agents
- CD28 Antigens
- CD57 Antigens
- CD8-Positive T-Lymphocytes
- Female
- HIV Infections
- Humans
- Lymphocyte Count
- Male
Keywords
- CD28
- CD57
- HIV
- Immunosenescence
- aging
- antiretroviral therapy
- immune activation
- mortality
Chronic antigenic stimulation by cytomegalovirus (CMV) is thought to increase "immunosenesence" of aging, characterized by accumulation of terminally differentiated CD28- CD8 T cells and increased CD57, a marker of proliferative history. Whether chronic HIV infection causes similar effects is currently unclear. We compared markers of CD8 T cell differentiation (e.g., CD28, CD27, CCR7, CD45RA) and CD57 expression on CD28- CD8 T cells in healthy HIV-uninfected adults with and without CMV infection and in both untreated and antiretroviral therapy (ART)-suppressed HIV-infected adults with asymptomatic CMV infection. Compared to HIV-uninfected adults without CMV (n=12), those with asymptomatic CMV infection (n=31) had a higher proportion of CD28-CD8 T cells expressing CD57 (P=0.005). Older age was also associated with greater proportions of CD28-CD8 T cells expressing CD57 (rho: 0.47, P=0.007). In contrast, untreated HIV-infected CMV participants (n=55) had much lower proportions of CD28- CD8 cells expressing CD57 than HIV-uninfected CMV participants (P<0.0001) and were enriched for less well-differentiated CD28- transitional memory (TTR) CD8 T cells (P<0.0001). Chronically HIV-infected adults maintaining ART-mediated viral suppression (n=96) had higher proportions of CD28-CD8 T cells expressing CD57 than untreated patients (P<0.0001), but continued to have significantly lower levels than HIV-uninfected controls (P=0.001). Among 45 HIV-infected individuals initiating their first ART regimen, the proportion of CD28-CD8 T cells expressing CD57 declined (P<0.0001), which correlated with a decline in percent of transitional memory CD8 T cells, and appeared to be largely explained by a decline in CD28-CD57- CD8 T cell counts rather than an expansion of CD28-CD57 CD8 T cell counts. Unlike CMV and aging, which are associated with terminal differentiation and proliferation of effector memory CD8 T cells, HIV inhibits this process, expanding less well-differentiated CD28- CD8 T cells and decreasing the proportion of CD28- CD8 T cells that express CD57.
MeSH Terms
- Adult
- Aging
- Antiretroviral Therapy, Highly Active
- CD28 Antigens
- CD57 Antigens
- CD8-Positive T-Lymphocytes
- Cross-Sectional Studies
- Cytomegalovirus
- Cytomegalovirus Infections
- Female
- HIV Infections
- HIV-1
- Humans
- Immunophenotyping
- Lymphocyte Count
- Male
- Middle Aged
Several contradictions and inconsistent reports regarding nature of dysfunction of immune system with age are known. The lack of multipoint age comparisons in immune functions contributes to the observed ambiguity in understanding immunosenescence. Thus, the present study aimed at a concurrent analysis of different immune cells in an attempt to delineate the nature of dysregulation with progressive aging in mice. 4, 8, 12 and 16 months old mice were analyzed for various immune parameters involving neutrophils, peripheral blood lymphocytes, peritoneal macrophages, splenocytes, inflamm-aging markers in plasma and humoral immune response in intestine. Neutrophils registered a remarkable decrease in activities of respiratory burst enzymes and phagocytosis, while macrophages recorded a decrease in TLR-2 and TLR-4 expression. MCP-1 and CRP levels increased in plasma, whereas stimulation index and CD28 expression decreased in lymphocytes. Interleukins analysis (IFN-γ, IL-4, IL-10) showed a remarkable shift towards Th2 response which further resulted in increased IgG1/IgG2a ratio and IgE levels in intestine. A decline in cell-mediated immune response, chronic inflammation and aggravation of humoral immunity was evident which conclusively suggests a skewed Th2 pathway during aging.
MeSH Terms
- Aging
- Animals
- Biomarkers
- CD28 Antigens
- Chemokine CCL2
- Immunity, Cellular
- Immunity, Humoral
- Immunoglobulins
- Inflammation
- Interferon-gamma
- Interleukin-10
- Interleukin-4
- Intestinal Mucosa
- Intestines
- Lymphocytes
- Macrophages
- Male
- Mice
- Neutrophils
- Phagocytosis
- Respiratory Burst
- Toll-Like Receptor 2
- Toll-Like Receptor 4
Cytomegalovirus (CMV) has been suggested as a contributing force behind the impaired immune responsiveness in the elderly, with decreased numbers of naïve T-cells and an increased proportion of effector T-cells. Immunological impairment is also implicated as a part of the pathogenesis in Alzheimer's disease (AD). The aim of this study was to investigate whether AD patients present with a different CMV-specific CD8 immune profile compared to non-demented controls. Blood samples from 50 AD patients and 50 age-matched controls were analysed for HLA-type, CMV serostatus and systemic inflammatory biomarkers. Using multi-colour flow cytometry, lymphocytes from peripheral blood mononuclear cells were analysed for CMV-specific CD8 immunity with MHC-I tetramers A01, A02, A24, B07, B08 and B35 and further classified using CD27, CD28, CD45RA and CCR7 antibodies. Among CMV seropositive subjects, patients with AD had significantly lower proportions of CMV-specific CD8 T-cells compared to controls, 1.16 % vs. 4.13 % (p=0.0057). Regardless of dementia status, CMV seropositive subjects presented with a lower proportion of naïve CD8 cells and a higher proportion of effector CD8 cells compared to seronegative subjects. Interestingly, patients with AD showed a decreased proportion of CMV-specific CD8 cells but no difference in general CD8 differentiation.
MeSH Terms
- Aged
- Aging
- Alzheimer Disease
- Antigens, CD
- CD4-CD8 Ratio
- CD8-Positive T-Lymphocytes
- Case-Control Studies
- Cell Differentiation
- Cytomegalovirus
- Female
- Flow Cytometry
- Humans
- Male
- Receptors, CCR7
Aging is associated with a profound reduction of the immune capacity (i.e., immunosenescence), which is manifested as increased morbidity and mortality due to infectious diseases in the elderly. The association of cytomegalovirus (CMV) with several aging-associated phenomena has been extensively characterized, e.g., the accumulation of CD8 nonproliferative, apoptosis-resistant memory cells that have lost the expression of the costimulatory molecule CD28. However, as the CMV seroprevalence is notably high in elderly individuals, the role of CMV-independent changes has been difficult to analyze. To address this question, we performed a transcriptomic analysis (Illumina Human HT12 microarray) of the peripheral blood mononuclear cells (PBMCs) in a cohort of 90-year-old individuals (CMV seronegative, n=6; CMV seropositive, n=140) using the PBMCs of young CMV-seronegative individuals (n=11) as the controls. The cell type distribution (CD3, CD4, CD8, CD28 and CD14) was analyzed using FACS. The data showed that the gene expression profiles of the CMV and CMV- nonagenarians were different compared to the CMV- controls. Compared to the CMV- controls, 667 genes showed altered expression in the CMV- nonagenarians, and 559 genes were altered in the CMV nonagenarians. Of these, 337 genes were common. An analysis of the canonical pathways revealed that the number of affected pathways was also different (42 in CMV-, 13 in CMV ; of these, 9 were common). Taken together, these results indicate that the CMV-dependent and CMV-independent changes in the aging of the immune system are fundamentally different.
MeSH Terms
- Adult
- Aged, 80 and over
- Aging
- Case-Control Studies
- Cytomegalovirus Infections
- Female
- Gene Expression Profiling
- Gene Expression Regulation
- Humans
- Leukocytes, Mononuclear
- Male
- Oligonucleotide Array Sequence Analysis
- Signal Transduction
- T-Lymphocyte Subsets
- Young Adult
As humans age, they experience a progressive loss of thymic function and a corresponding shift in the makeup of the circulating CD8 T cell population from naïve to memory phenotype. These alterations are believed to result in impaired CD8 T cell responses in older individuals; however, evidence that these global changes impact virus-specific CD8 T cell immunity in the elderly is lacking. To gain further insight into the functionality of virus-specific CD8 T cells in older individuals, we interrogated a cohort of individuals who were acutely infected with West Nile virus (WNV) and chronically infected with Epstein Barr virus (EBV) and Cytomegalovirus (CMV). The cohort was stratified into young (<40 yrs), middle-aged (41-59 yrs) and aged (>60 yrs) groups. In the aged cohort, the CD8 T cell compartment displayed a marked reduction in the frequency of naïve CD8 T cells and increased frequencies of CD8 T cells that expressed CD57 and lacked CD28, as previously described. However, we did not observe an influence of age on either the frequency of virus-specific CD8 T cells within the circulating pool nor their functionality (based on the production of IFNγ, TNFα, IL2, Granzyme B, Perforin and mobilization of CD107a). We did note that CD8 T cells specific for WNV, CMV or EBV displayed distinct functional profiles, but these differences were unrelated to age. Collectively, these data fail to support the hypothesis that immunosenescence leads to defective CD8 T cell immunity and suggest that it should be possible to develop CD8 T cell vaccines to protect aged individuals from infections with novel emerging viruses.
MeSH Terms
- Adult
- Aged
- Aged, 80 and over
- Aging
- CD57 Antigens
- CD8-Positive T-Lymphocytes
- Chronic Disease
- Cohort Studies
- Cytokines
- Female
- Granzymes
- Humans
- Immunologic Memory
- Lysosomal-Associated Membrane Protein 1
- Male
- Middle Aged
- Viral Vaccines
- Virus Diseases
Previous in vitro studies showed that CD4 T cells from old mice have defects in TCR signaling, immune synapse formation, activation, and proliferation. We reported that removing a specific set of surface glycoproteins by ex vivo treatment with O-sialoglycoprotein endopeptidase (OSGE) can reverse many aspects of the age-related decline in CD4 T cell function. However, the specific mechanism by which this process occurs remains unclear, and it is unknown whether this enzymatic treatment can also restore important aspects of adaptive immunity in vivo. By using an in vivo model of the immune response based on adoptive transfer of CD4 T cells from pigeon cytochrome C-specific transgenic H-2(k/k) TCR-Vα(11)Vβ(3) CD4( ) mice to syngeneic hosts, we demonstrate that aging diminishes CD28 costimulatory signals in CD4 T cells. These age-associated defects include changes in phosphorylation of AKT and expression of glucose transporter type I, inducible T cell costimulatory molecule, and CD40L, suggesting that the lack of CD28 costimulation contributes to age-dependent loss of CD4 function. All of these deficits can be reversed by ex vivo OSGE treatment. Blocking B7-CD28 interactions on T cells prevents OSGE-mediated restoration of T cell function, suggesting that changes in surface glycosylation, including CD28, may be responsible for the age-related costimulation decline. Finally, we show that the age-related decline in CD4 cognate helper function for IgG production and long-term humoral immunity can also be restored by OSGE treatment of CD4 T cells prior to adoptive transfer.
MeSH Terms
- Adoptive Transfer
- Aging
- Animals
- Antibody Specificity
- CD4-Positive T-Lymphocytes
- Cell Proliferation
- Cellular Senescence
- Immunoglobulin G
- Lymphocyte Activation
- Metalloendopeptidases
- Mice
- Mice, Inbred BALB C
- Mice, Inbred C57BL
- Mice, Knockout
- Mice, Transgenic
- Up-Regulation
The decline of the immune system appears to be an intractable consequence of aging, leading to increased susceptibility to infections, reduced effectiveness of vaccination and higher incidences of many diseases including osteoporosis and cancer in the elderly. These outcomes can be attributed, at least in part, to a phenomenon known as T cell replicative senescence, a terminal state characterized by dysregulated immune function, loss of the CD28 costimulatory molecule, shortened telomeres and elevated production of proinflammatory cytokines. Senescent CD8 T cells, which accumulate in the elderly, have been shown to frequently bear antigen specificity against cytomegalovirus (CMV), suggesting that this common and persistent infection may drive immune senescence and result in functional and phenotypic changes to the T cell repertoire. Senescent T cells have also been identified in patients with certain cancers, autoimmune diseases and chronic infections, such as HIV. This review discusses the in vivo and in vitro evidence for the contribution of CD8 T cell replicative senescence to a plethora of age-related pathologies and a few possible therapeutic avenues to delay or prevent this differentiative end-state in T cells. The age-associated remodeling of the immune system, through accumulation of senescent T cells has farreaching consequences on the individual and society alike, for the current healthcare system needs to meet the urgent demands of the increasing proportions of the elderly in the US and abroad.
MeSH Terms
- Aging
- Cellular Senescence
- Humans
- Lymphocyte Activation
- T-Lymphocytes
- Telomere
As perinatally HIV-1-infected children grow into adolescents and young adults, they are increasingly burdened with the long-term consequences of chronic HIV-1 infection, with long-term morbidity due to inadequate immunity. In progressive HIV-1 infection in horizontally infected adults, inflammation, T cell activation, and perturbed T cell differentiation lead to an "immune exhaustion", with decline in T cell effector functions. T effector cells develop an increased expression of CD57 and loss of CD28, with an increase in co-inhibitory receptors such as PD-1 and Tim-3. Very little is known about HIV-1 induced T cell dysfunction in vertical infection. In two perinatally antiretroviral drug treated HIV-1-infected groups with median ages of 11.2 yr and 18.5 yr, matched for viral load, we found no difference in the proportion of senescent CD28(-)CD57( )CD8( ) T cells between the groups. However, the frequency of Tim-3( )CD8( ) and Tim-3( )CD4( ) exhausted T cells, but not PD-1( ) T cells, was significantly increased in the adolescents with longer duration of infection compared to the children with shorter duration of HIV-1 infection. PD-1( )CD8( ) T cells were directly associated with T cell immune activation in children. The frequency of Tim-3( )CD8( ) T cells positively correlated with HIV-1 plasma viral load in the adolescents but not in the children. These data suggest that Tim-3 upregulation was driven by both HIV-1 viral replication and increased age, whereas PD-1 expression is associated with immune activation. These findings also suggest that the Tim-3 immune exhaustion phenotype rather than PD-1 or senescent cells plays an important role in age-related T cell dysfunction in perinatal HIV-1 infection. Targeting Tim-3 may serve as a novel therapeutic approach to improve immune control of virus replication and mitigate age related T cell exhaustion.
MeSH Terms
- Aging
- Child
- HIV Infections
- HIV-1
- Hepatitis A Virus Cellular Receptor 2
- Humans
- Infectious Disease Transmission, Vertical
- Membrane Proteins
- T-Lymphocytes
- Viral Load
Prolonged survival in HIV infection is accompanied by an increased frequency of non-HIV-related comorbidities. A number of age-related comorbidities occur earlier in HIV-infected patients than in individuals without HIV infection. This "accelerated aging" appears to be largely related to chronic inflammation, chronic immune activation, and immunosenescence in HIV infection. Levels of markers of inflammation and coagulopathy are elevated in HIV-infected patients, and elevations in markers such as high-sensitivity C-reactive protein, D-dimer, and interleukin 6 (IL-6) have been associated with increased risk for cardiovascular disease, opportunistic conditions, or all-cause mortality. In both HIV infection and aging, immunosenescence is marked by an increased proportion of CD28-, CD57 memory CD8 T cells with reduced capacity to produce interleukin 2 (IL-2), increased production of IL-6, resistance to apoptosis, and shortened telomeres. A number of AIDS Clinical Trials Group studies are under way to examine treatment aimed at reducing chronic inflammation and immune activation in HIV infection. This article summarizes a presentation by Judith A. Aberg, MD, at the IAS-USA live continuing medical education course held in New York City in October 2011.
MeSH Terms
- Aging
- CD28 Antigens
- CD57 Antigens
- CD8-Positive T-Lymphocytes
- Chronic Disease
- Comorbidity
- HIV Infections
- Humans
- Immunologic Memory
- Inflammation
- Interleukin-2
- Interleukin-6
- New York City
- T-Lymphocyte Subsets
- Telomere
- United States
CD8 T cells stimulated with a suboptimal dose of anti-CD3 Abs (100 pg/ml) in the presence of IL-15 retain a naive phenotype with expression of CD45RA, CD28, CD27, and CCR7 but acquire new functions and differentiate into immunosuppressive T cells. CD8 CCR7 regulatory T cells (Tregs) express FOXP3 and prevent CD4 T cells from responding to TCR stimulation and entering the cell cycle. Naive CD4 T cells are more susceptible to inhibition than memory cells. The suppressive activity of CD8 CCR7 Tregs is not mediated by IL-10, TGF-β, CTLA-4, CCL4, or adenosine and relies on interference with very early steps of the TCR signaling cascade. Specifically, CD8 CCR7 Tregs prevent TCR-induced phosphorylation of ZAP70 and dampen the rise of intracellular calcium in CD4 T cells. The inducibility of CD8 CCR7 Tregs is correlated with the age of the individual with PBLs of donors older than 60 y yielding low numbers of FOXP3(low) CD8 Tregs. Loss of CD8 CCR7 Tregs in the elderly host may be of relevance in the aging immune system as immunosenescence is associated with a state of chronic smoldering inflammation.
MeSH Terms
- Adolescent
- Adult
- Aged
- Aged, 80 and over
- Aging
- CD8 Antigens
- Cell Death
- Cell Differentiation
- Forkhead Transcription Factors
- Humans
- Immune Tolerance
- Leukocyte Common Antigens
- Middle Aged
- Primary Cell Culture
- Receptors, CCR7
- T-Lymphocyte Subsets
- T-Lymphocytes, Regulatory
The immune system changes with age. In this study we characterized immune changes by performing immunologic screening profiles on ageing individuals. This study was performed at Akdeniz University, in the Faculty of Medicine, Department of Immunology. Healthy volunteers consisted of a younger group (22 donors) and an older group (45 individuals). All subjects had no serious health problems (i.e. chronic heart, lung, liver or immunological diseases) and were taking no prescribed medications. Flow cytometry analysis was used to evaluate CD3, CD4, CD8, CD16, CD19, CD28, CD40, CD45, CD56, CD80, CD86, CTLA-4 and ELISA for IL-1 beta, IL-2, IL-6, IL-10, IFN-gamma, TNF-alpha expression In addition, NK activity and induced cytokine expression (by bioassay and ELISA, respectively) were evaluated. No statistical differences were observed between the two groups in expression of CD3, CD8, CD19, CD80, CD86, CD16, CD 56, or CD28. A higher frequency of expression of CD4, CTLA-4, CD40, and CD45 was seen in older subjects by comparison with younger subjects. Cytokine profiles expressed by stimulated monocytes and lymphocytes from the two groups showed no difference in IL-1 beta, IL-2, IL-6, IL-10, TNF-alpha, and IFN-gamma production levels. We found increased expression levels of CD40 and CD45 levels in healthy older (age: 59.42 /- 5.89) versus younger individuals (age: 30.32 /- 2.29). CTLA-4 expression levels were also higher in older subjects, with no difference in CD28 expression levels between younger/older individuals.
MeSH Terms
- Adult
- Age Factors
- Aging
- Biomarkers
- CD40 Antigens
- CTLA-4 Antigen
- Cytokines
- Female
- Flow Cytometry
- Humans
- Immunity, Humoral
- Leukocyte Common Antigens
- Lymphocytes
- Male
- Middle Aged
- Monocytes
The low percentages of naïve T cells commonly observed in elderly people are thought to be causally associated with mortality, primarily from infectious disease, and are taken as a hallmark of "immunosenescence". Whether low levels of naive cells actually do associate with mortality has, however, not been tested in longitudinal studies. Here, we present correlations between peripheral T-cell phenotypes and 8-year survival in individuals from the population-based prospective Leiden 85-plus Study. Counter-intuitively, we found that a lower frequency of naïve CD8 T cells (characterized as CD45RA CCR7 CD27 CD28 ) at baseline (>88 years) correlated with significantly better survival, while there was a tendency for the reciprocal accumulation of late-differentiated effector memory cells (CD45RA-CCR7-CD27-CD28-) also to associate with better survival. These findings suggest that better retention of memory cells specific for previously encountered antigens may provide a survival advantage in this particular population. Given the prevalence of Cytomegalovirus (CMV) and its reported association with immunosenescence, we tested whether memory for this potential pathogen was relevant to survival. We found that individuals mounting an exclusively pro-inflammatory ex vivo response (TNF, IFN-γ, IL-17) to the major CMV target molecules pp65 and IE1 had a significant survival advantage over those also having anti-inflammatory responses (IL-10). These findings suggest that higher levels of naïve T cells may not necessarily be associated with a survival advantage and imply that the nature of immunosurveillance against CMV may be crucial for remaining longevity, at least in the very elderly.
MeSH Terms
- Aged, 80 and over
- Aging
- Antigens, Viral
- CD8-Positive T-Lymphocytes
- Cytomegalovirus
- Female
- Flow Cytometry
- Follow-Up Studies
- Humans
- Immunity, Cellular
- Longevity
- Male
- Netherlands
- Population Surveillance
- Prospective Studies
- Survival Rate
- Viral Proteins
Few data have been acquired on the predictive value of age-related T-lymphocyte subsets among older individuals. The present study has determined the distribution of T-cell phenotypes and their correlation to 2-year mortality in a cohort of Chinese male seniors. A total of 101 asymptomatic elderly individuals with laboratory homeostasis were enrolled at baseline. Three age subgroups were categorized as young (65 - 74 years old), middle (75 - 84 years old), and old (≥ 85 years) for age-related comparison. T-cell subsets in peripheral blood were measured by multi-colored flow cytometry. At baseline, there was a mild negative correlation by age for total lymphocytes and CD3( ) T-cells. The frequency of CD28 and CD95 demonstrated a "curved" rather than linear tendency by age. At 2-year follow-up, little change of T-cell distribution was found among those who remained alive (as survivors) comparing the data at baseline to the 2-year time point. Immune risk phenotypes were distinctly demonstrated between survivors and non-survivors. Since few studies have studied on the distribution of T-lymphocyte subsets in an elderly Chinese population, our results have not only provided reference values of T-subsets for aged Chinese men, but confirmed the immune risk phenotypes among elderly Chinese. The inappropriate age-dependent trajectory of CD28(-)/CD8( ) and CD95(-)/CD8( ) by age, which suggested 85 might be an inflexion point of age during T-cell ageing, warrants further exploration of the underlying mechanisms of T-cell ageing.
MeSH Terms
- Aged
- Aged, 80 and over
- Aging
- CD4-CD8 Ratio
- Cellular Senescence
- China
- Cohort Studies
- Cross-Sectional Studies
- Humans
- Longitudinal Studies
- Male
- Mortality
- T-Lymphocyte Subsets
The increasing number of elderly people eligible for solid organ transplants has made it necessary to reevaluate how the decline in immune function associated to ageing (immunosenescence) affects solid organ transplants. Some immunosenescence biomarkers, such as the expansion of CD28(-)CD8 T lymphocytes, have been associated to cytomegalovirus infection and are related to a form of accelerated immune senescence in transplant recipients. However, the impact of cytomegalovirus replication on downregulation of CD28 on total CD8 T cells is independent of patients' age, whereas downregulation on cytomegalovirus-specific CD8 T cells depends on patients' age, inducing early immunosenescence of cytomegalovirus-specific CD8 T cells in young but not elderly solid organ transplants recipients. Although immunosenescence in transplant recipients should be considered a two-edged sword as it is a risk factor for the development of tumors after transplantation, it has a beneficial effect in attenuating acute allograft rejection and correlates with better clinical outcomes.
MeSH Terms
- Aged
- Aging
- CD28 Antigens
- CD8-Positive T-Lymphocytes
- Cellular Senescence
- Cytomegalovirus
- Cytomegalovirus Infections
- Humans
- Immune Tolerance
- Models, Immunological
- Neoplasms
- Risk Factors
- Transplantation Immunology
- Transplants
- Virus Replication
With increasing age, the ability of the immune system to protect against new antigenic challenges or to control chronic infections erodes. Decline in thymic function and cumulating antigenic experiences of acute and chronic infections threaten T cell homeostasis, but insufficiently explain the failing immune competence and the increased susceptibility for autoimmunity. Alterations in signaling pathways in the aging T cells account for many of the age-related defects. Signaling threshold calibrations seen with aging frequently built on mechanisms that are operational in T cell development and T cell differentiation or are adaptations to the changing environment in the aging host. Age-related changes in transcription of receptors and signaling molecules shift the balance towards inhibitory pathways, most dominantly seen in CD8 T cells and to a lesser degree in CD4 T cells. Prominent examples are the expression of negative regulatory receptors of the CD28 and the TNF receptor superfamilies as well the expression of various cytoplasmic and nuclear dual-specific phosphatases.
MeSH Terms
- Aging
- Animals
- Cell Differentiation
- Cellular Senescence
- Humans
- Receptors, Antigen, T-Cell
- Signal Transduction
- T-Lymphocytes
To establish subacute aging mice model by D-galactose and to explore the changes and effects of significant membrane molecules on thymic T cell. Female Kunming mice of 8 weeks old were injected with D-galactose of 12.5 mL/(kg.d) by subcutaneous in scruff for 42 days. The animals' living conditions and biological behaviors were observed everyday.SOD activities and MDA content of serum were measured to determine whether the aging model was successfully established.On the basis of successfully establishing aging model, detect the significant membrane molecules of thymic T cell by Immunofluorescence technique and Flow Cytometer. During the 42 days, gradually, the model mice showed bending body, loose skin, slow action and so on.The activities of SOD in the serum were significantly decreased(P<0.01), and the content of MDA in the serum was significantly increased(P<0.01). The thymic naive T cell significant molecule, CD45RA was decreased(P<0.05). T cell activation-related molecules, CD28 and CD25 were both decreased(P<0.05), and PD-1 was significantly increased(P<0.01). The memory T cell significant molecule, CD196 was increased, but was not significantly compared to the control mice. The D-galactose subacute aging mice model was successfully established.The naive and active T cell were decreased and the memory T cell was increased in the thymic of the aging.
MeSH Terms
- Aging
- Animals
- Cell Membrane
- Female
- Galactose
- Immunologic Memory
- Lymphocyte Activation
- Malondialdehyde
- Mice
- Superoxide Dismutase
- T-Lymphocytes
- Thymocytes
The health of old monkeys usually begins to deteriorate by 20 years of age, coinciding with the onset of a slowly progressing immune senescence. Changes in lymphocyte subsets and responses to several antigens have been characterized in geriatric primates, but systematic research has not been conducted on vaccination against influenza virus, a topic of considerable clinical concern for elderly humans. Antibody responses were significantly reduced to primary immunizations in old monkeys, but by administering a second vaccine at 1 month, it was possible to boost antibody titers up to the level found in young adults during their primary phase. The immune competence of unusually long-lived animals (26-37 years) was also compared to more typical aged monkeys (19-25 years). Antibody responses were low overall, although some monkeys in both age groups did respond to immunization. Among the oldest animals, the leukocytes of the responders with higher antibody titers were found to release more interleukin-2 following in vitro stimulation with an anti-CD3/anti-CD28 cocktail relative to their cellular reactions to staphylococcal enterotoxin B. The general decline in immune vigor, and the marked individual variation in how old monkeys age, provides a useful animal model for investigating factors associated with immunosenescence.
MeSH Terms
- Age Factors
- Aging
- Animals
- Antibodies, Viral
- Antibody Formation
- Female
- Follow-Up Studies
- Immunity, Innate
- Influenza Vaccines
- Macaca mulatta
- Male
- Orthomyxoviridae
- Orthomyxoviridae Infections
- Vaccination
CD28-, CD57 and KLRG1 are cell surface markers that have been used to describe senescent T-lymphocytes in humans. However, the relationship among these phenotypes during aging, and their relationship with the concept of in vitro cellular aging have not been well established. Using five-colour flow cytometry, we analyzed peripheral blood T-lymphocytes for their expression of CD28, CD57 and KLRG1 in 11 young (Y) and 11 old (O) apparently healthy human subjects. The proportions of CD28- and CD57 cells were significantly higher among the T-cell populations of O compared to Y subjects; the proportion of KLRG1 cells was significantly higher only among CD8 cells. Populations that were more frequent in the elderly participants were characterised as CD28 CD57 , CD28- CD57 or CD28- CD57-. The expression of p16 and p21, considered as markers for in vitro senescence, was higher in CD28 CD57 cells than in other subpopulations in both age groups. The expression of p21 was age-related, which was not the case for p16. Thus, although both p16 and p21 are involved in T-cell senescence, they appear to behave differently. CMV infection and shifts in subpopulations are unlikely as explanations of the observed differences. Their higher levels of p16 and p21 expression, coupled with their higher prevalence in the elderly participants make CD28 CD57 cells the subpopulation of T-cells most closely corresponding to the concept of senescent cells.
MeSH Terms
- Adult
- Age Factors
- Aged
- Aging
- Biomarkers
- CD28 Antigens
- CD57 Antigens
- Cell Proliferation
- Cellular Senescence
- Cyclin-Dependent Kinase Inhibitor p16
- Cyclin-Dependent Kinase Inhibitor p21
- Female
- Flow Cytometry
- Humans
- Immunophenotyping
- Lectins, C-Type
- Male
- Phenotype
- Receptors, Immunologic
- T-Lymphocyte Subsets
- Trans-Activators
- Young Adult
Non-melanoma skin cancers are a common reality worldwide. The principal cause that determines the occurrence of these diseases is the exposition of the sun, which principally causes an alteration in the immune system. Therefore, it is possible that other forms of innate or acquired alterations of the immune system could favor the occurrence of non-melanoma skin cancers. For example, several studies have demonstrated that immunosenescence creates an immunosuppressive state that encourages the development of malignances, and new discoveries have noted the importance of T cells and in particular of T regulatory cells (Treg) and T receptor CD28 in this mechanism. Similar results are obtained analyzing the effect of immunosuppressive drugs. The importance of the immune system and its alteration in the genesis of non-melanoma skin cancers is fundamental for the creation of a new therapeutic and less invasive approach.
MeSH Terms
- Aged
- Aged, 80 and over
- Aging
- Humans
- Immunosuppressive Agents
- Immunotherapy
- Skin Neoplasms
The abundance of a preselection of transcripts involved in inflammation, immunosenescence and stress response was compared between PBMC of healthy aged donors and aged patients in acute phase of heart failure and at recovery. This study identified 22 transcripts differentially abundant in acute phase of heart failure versus healthy aged subjects. Transcripts involved in inflammation and oxidative stress were more abundant. Those associated with T-cell functions were less abundant. The results were compared to two other major acute geriatric issues: infectious diseases and hip fracture. In acute phase, compared to healthy aged subjects, the abundance of 15/22 transcripts was also altered in both geriatric infectious diseases and hip fracture. Many variations had not vanished at the recovery phase. The abundance of CD28, CD69, LCK, HMOX1, TNFRSF1A transcripts, known to be altered in healthy aged versus healthy young subjects, was further affected in acute phase of the three geriatric diseases considered. The transcript levels of BCL2, CASP8, CCL5, [[DDIT3]], EGR3, IL10RB, IL1R2, SERPINB2 and TIMP1 were affected in all three pathological conditions compared to healthy aged, but not versus healthy young subjects. In conclusion, this work provides critical targets for therapeutic research on geriatric heart failure, infectious diseases and hip fracture.
MeSH Terms
- Adult
- Aged
- Aged, 80 and over
- Aging
- Biomarkers
- Communicable Diseases
- Female
- Heart Failure
- Hip Fractures
- Hospitalization
- Humans
- Male
- Neutrophils
- Transcription, Genetic
Sarcopenia is the age-associated loss of skeletal muscle mass and strength. Recent evidence suggests that an age-associated loss of muscle precursor cell (MPC) functionality contributes to sarcopenia. The objectives of the present study were to examine the influence of activated T cells on MPCs and determine whether an age-related defect in this signaling occurs. MPCs were collected from the gastrocnemius and plantaris of 3-mo-old (young) and 32-mo-old (old) animals. Splenic T cells were harvested using anti-CD3 Dynabead isolation. T cells were activated for 48 h with costimulation of 100 IU/ml interleukin-2 (IL-2) and 5 μg/ml of anti-CD28. Costimulation increased 5-bromo-2'-deoxyuridine incorporation of T cells from 13.4 ± 4.6% in control to 64.8 ± 6.0% in costimulated cells. Additionally, T cell cytokines increased proliferation on MPCs isolated from young muscle by 24.0 ± 5.7%, whereas there was no effect on MPCs isolated from aged muscle. T cell cytokines were also found to be a chemoattractant. T cells were able to promote migration of MPCs isolated from young muscle; however, MPCs isolated from aged muscle did not respond to the T cell-released chemokines. Conversely, whereas T cell-released cytokines did not affect myogenesis of MPCs isolated from young animals, there was a decrease in MPCs isolated from old animals. These data suggest that T cells may play a critical role in mediating MPC function. Furthermore, aging may alter T cell-induced MPC function. These findings have implications for developing strategies aimed at increasing MPC migration and proliferation leading to an improved regenerative capacity of aged skeletal muscle.
MeSH Terms
- Aging
- Animals
- Cell Differentiation
- Cell Movement
- Cell Proliferation
- Cells, Cultured
- Cytokines
- Humans
- Muscle Development
- Muscle, Skeletal
- Precursor Cells, T-Lymphoid
- Rats
- Rats, Inbred F344
- T-Lymphocytes
Human aging is characterized by changes in the immune system which have a profound impact on the T-cell compartment. These changes are more frequently found in CD8 T cells, and there are not well-defined markers of differentiation in the CD4 subset. Typical features of cell immunosenescence are characteristics of pathologies in which the aberrant expression of NKG2D in CD4 T cells has been described. To evaluate a possible age-related expression of NKG2D in CD4 T cells, we compared their percentage in peripheral blood from 100 elderly and 50 young adults. The median percentage of CD4 NKG2D in elders was 5.3% (interquartile range (IR): 8.74%) versus 1.4% (IR: 1.7%) in young subjects (p < 0.3 × 10(-10)). CD28 expression distinguished two subsets of CD4 NKG2D cells with distinct functional properties and differentiation status. CD28 cells showed an immature phenotype associated with high frequencies of CD45RA and CD31. However, most of the NKG2D cells belonged to the CD28(null) compartment and shared their phenotypical properties. NKG2D cells represented a more advanced stage of maturation and exhibited greater response to CMV (5.3 ± 3.1% versus 3.4 ± 2%, p = 0.037), higher production of IFN-γ (40.56 ± 13.7% versus 24 ± 8.8%, p = 0.015), lower activation threshold and reduced TREC content. Moreover, the frequency of the CD4 NKG2D subset was clearly related to the status of the T cells. Higher frequencies of the NKG2D subset were accompanied with a gradual decrease of NAIVE and central memory cells, but also with a higher level of more differentiated subsets of CD4 T cells. In conclusion, CD4 NKG2D represent a subset of highly differentiated T cells which characterizes the senescence of the immune system.
MeSH Terms
- Adolescent
- Adult
- Aged
- Aged, 80 and over
- Aging
- Antigens, Viral
- CD4-Positive T-Lymphocytes
- CD8-Positive T-Lymphocytes
- Cytomegalovirus
- Female
- Humans
- Immunologic Memory
- Immunophenotyping
- Influenza Vaccines
- Male
- Middle Aged
- NK Cell Lectin-Like Receptor Subfamily K
- T-Lymphocyte Subsets
- Young Adult
The relative roles that ageing and lifelong cytomegalovirus (CMV) infection have in shaping naive and memory CD4 T-cell repertoires in healthy older people is unclear. Using multiple linear regression analysis we found that age itself is a stronger predictor than CMV seropositivity for the decrease in CD45RA CD27 CD4 T cells over time. In contrast, the increase in CD45RA⁻ CD27⁻ and CD45RA CD27⁻ CD4 T cells is almost exclusively the result of CMV seropositivity, with age alone having no significant effect. Furthermore, the majority of the CD45RA⁻ CD27⁻ and CD45RA CD27⁻ CD4 T cells in CMV-seropositive donors are specific for this virus. CD45RA CD27⁻ CD4 T cells have significantly reduced CD28, interleukin-7 receptor α (IL-7Rα) and Bcl-2 expression, Akt (ser473) phosphorylation and reduced ability to survive after T-cell receptor activation compared with the other T-cell subsets in the same donors. Despite this, the CD45RA CD27⁻ subset is as multifunctional as the CD45RA⁻ D27 and CD45RA⁻ CD27⁻ CD4 T-cell subsets, indicating that they are not an exhausted population. In addition, CD45RA CD27⁻ CD4 T cells have cytotoxic potential as they express high levels of granzyme B and perforin. CD4 memory T cells re-expressing CD45RA can be generated from the CD45RA⁻ CD27 population by the addition of IL-7 and during this process these cells down-regulated expression of IL-7R and Bcl-2 and so resemble their counterparts in vivo. Finally we showed that the proportion of CD45RA CD27⁻ CD4 T cells of multiple specificities was significantly higher in the bone marrow than the blood of the same individuals, suggesting that this may be a site where these cells are generated.
MeSH Terms
- Adult
- Aged
- Aged, 80 and over
- Aging
- CD4-Positive T-Lymphocytes
- Cell Differentiation
- Cell Separation
- Cell Survival
- Cytomegalovirus Infections
- Flow Cytometry
- Humans
- Interleukin-7
- Leukocyte Common Antigens
- Middle Aged
- Signal Transduction
- T-Lymphocyte Subsets
- Tumor Necrosis Factor Receptor Superfamily, Member 7
- Young Adult
The abundance of a selection of transcript species involved in inflammation, immunosenescence and stress response was compared between PBMC of 35 geriatric patients with hip fracture in acute phase (days 2-4 after hospitalization) or convalescence phase (days 7-10) and 28 healthy aged controls. Twenty-nine differentially abundant transcripts were identified in acute phase versus healthy ageing. Twelve of these transcripts remained differentially abundant in convalescence phase, and 22 were similarly differentially abundant in acute phase of geriatric infectious diseases. Seven of these 22 transcripts were previously identified as differentially abundant in PBMC of healthy aged versus healthy young controls, with further alteration for CD28, CD69, LCK, CTSD, HMOX1, and TNFRSF1A in acute phase after geriatric hip fracture and infectious diseases. The next question is whether these alterations are common to other geriatric diseases and/or preexist before the clinical onset of the diseases.
MeSH Terms
- Acute-Phase Reaction
- Adult
- Aged
- Aged, 80 and over
- Aging
- Antigens, CD
- Antigens, Differentiation, T-Lymphocyte
- Base Sequence
- CD28 Antigens
- Case-Control Studies
- Cathepsin D
- DNA Primers
- Female
- Gene Expression Profiling
- Heme Oxygenase-1
- Hip Fractures
- Hospitalization
- Humans
- Lectins, C-Type
- Leukocytes, Mononuclear
- Lymphocyte Specific Protein Tyrosine Kinase p56(lck)
- Male
- Receptors, Tumor Necrosis Factor, Type I
Decreased immune responsiveness associated with aging is generally termed "immunosenescence". Several theories have been proposed to explain age-related declines in immune responses. Here, we will focus on and describe potential defects in T cell signal transduction from the membrane to the nucleus, leading to changes in the type, intensity and duration of the response as a major factor contributing to immunosenescence. We will first detail T cell signaling through the T cell receptor (TCR), CD28 and IL-2 receptor (IL-2R) and then discuss the observed age-related alterations to these signaling pathways. The role of membrane rafts in T cell signaling and T cell aging will be described. These factors will be considered in the context of the notion that age-related changes to T cell signaling may be attributed to changes in the functionality of the T cells due to shifts in T cell subpopulations with age. For this reason, we conclude by highlighting the application of multiparametric signaling analysis in leukocyte subsets using flow cytometry as a means to obtain a clearer picture with respect to age-related changes to immune signaling.
MeSH Terms
- Aged
- Aged, 80 and over
- Aging
- Cellular Senescence
- Homeostasis
- Humans
- Membrane Microdomains
- Signal Transduction
- T-Lymphocytes
The integration and control of systemic immune responses depends on the regulated trafficking of T-lymphocytes. This study elucidates how various exercises regimens with/without hypoxia affect phenotypic characteristics of T-lymphocyte subsets in blood. Fifty sedentary males were randomly divided into five groups. Each group (n=10) received one of five interventions: normoxic (21%O₂) resting (N-C), hypoxic (15%O₂) resting (H-C), normoxic exercise (50%W(max) under 21%O₂, N-T), hypoxic-relative exercise (50% maximal heart rate reserve under 15%O₂, H-RT), or hypoxic-absolute exercise (50%W(max) under 15%O₂, H-AT) for 30 min/day, 5 days/week for 4 weeks. Before the intervention, strenuous exercise up to exhaustion increased the mobilization of CD3, CD4, CD8, or CD8(bright) lymphocytes expressing activated (CD11a) or senescent (KLRG1) molecules into the peripheral blood compartment. The H-AT for 4 weeks up-regulated co-stimulatory molecule CD28 expression and was accompanied by depressed KLRG1 level on CD3, CD4, CD8, or CD8(bright) lymphocytes at rest or following exercise. Simultaneously, this intervention increased interferon-γ (IFN-γ) level and unchanged interleukin-4 level, as well as, decreased myeloperoxidase (MPO) and interleukin-6 levels in plasma. However, no significant changes in resting and exercise-induced mobilizations of various T-lymphocyte subsets and productions of cytokines and MPO occurred following the N-C, H-C, N-T, and H-RT interventions. Therefore, we conclude that 4-week H-AT intervention reduced senescent T-lymphocyte subsets with increasing IFN-γ level in blood, which responses are accompanied by depressed oxidative stress and pro-inflammatory cytokine production. These findings can help to determine an effective hypoxic exercise regimen to minimize immune dysfunction by retarding T-lymphocyte senescence.
MeSH Terms
- Adult
- Aging
- CD3 Complex
- CD4 Lymphocyte Count
- CD8-Positive T-Lymphocytes
- Catecholamines
- Exercise
- Exercise Test
- Humans
- Hypoxia
- Interferon-gamma
- Interleukin-4
- Interleukin-6
- Lymphocyte Count
- Male
- Membrane Glycoproteins
- Memory
- Peroxidase
- Phenotype
- Physical Fitness
- T-Lymphocyte Subsets
- Th1 Cells
- Th2 Cells
- Young Adult
The CD28 gene is similarly down-regulated in CD4( ) lymphocytes from both healthy elderly people and patients with rheumatoid arthritis (RA) because of impaired protein-binding activity of the 'α' sequence in its promoter region. Other genes important for the CD4( ) cell function may share that sequence and may be similarly regulated and affected. We searched GenBank for possible 'α' homologues and then compared transcriptional activities of the respective genes in the CD4( ) cells of young and older healthy individuals and those with RA by real-time PCR. We show here that genes encoding one of the zinc finger proteins (ZNF334), the 'aging hormone' Klotho, the retinoid acid receptor β2 (RARβ2) and the T-cell adapter protein GRAP-2, contain sequences with various (exceeding 70%) degrees of homology to the 'α' sequence near their promoters. These genes are transcribed in human CD4( ) lymphocytes; the expressions of RARβ2, KLOTHO and ZNF334 are significantly decreased in a correlated manner in the cells of patients with RA compared with those of healthy individuals. In RA patients, the extremely reduced expression of ZNF334 does not depend on the individual's age, apparently constituting a disease-related phenomenon; whereas that of RARβ2 and KLOTHO occurs mostly in the cells of relatively younger patients, making them similar to the lymphocytes of healthy elderly in this aspect.
MeSH Terms
- Adaptor Proteins, Signal Transducing
- Adult
- Aged
- Aged, 80 and over
- Aging
- Amino Acid Sequence
- Arthritis, Rheumatoid
- CD28 Antigens
- CD4-Positive T-Lymphocytes
- Gene Expression Profiling
- Gene Expression Regulation
- Glucuronidase
- Humans
- Middle Aged
- Molecular Sequence Data
- Promoter Regions, Genetic
- Receptors, Retinoic Acid
- Reverse Transcriptase Polymerase Chain Reaction
- Sequence Homology, Amino Acid
- Transcription, Genetic
- Young Adult
CD28 costimulatory signal transduction in T lymphocytes is essential for optimal telomerase activity, stabilization of cytokine mRNAs, and glucose metabolism. During aging and chronic infection with HIV-1, there are increased proportions of CD8 T lymphocytes that lack CD28 expression and show additional features of replicative senescence. Moreover, the abundance of these cells correlates with decreased vaccine responsiveness, early mortality in the very old, and accelerated HIV disease progression. Here, we show that sustained expression of CD28, via gene transduction, retards the process of replicative senescence, as evidenced by enhanced telomerase activity, increased overall proliferative potential, and reduced secretion of pro-inflammatory cytokines. Nevertheless, the transduced cultures eventually do reach senescence, which is associated with increased CTLA-4 gene expression and a loss of CD28 cell surface expression. These findings further elucidate the central role of CD28 in the replicative senescence program, and may ultimately lead to novel therapies for diseases associated with replicative senescence.
MeSH Terms
- Aging
- Animals
- CD28 Antigens
- CD8-Positive T-Lymphocytes
- Cellular Senescence
- Disease Progression
- Gene Expression Regulation
- HIV Infections
- Humans
- Signal Transduction
Programmed cell death-1 (PD-1) is a newly characterized negative regulator of immune responses. The interaction of PD-1 with its ligands (PD-L1 and PD-L2) inhibits T-cell proliferation and cytokine production in young mice. Increased PD-1 expression has been described during chronic infections, inducing chronic activation of the immune system to control it. As aging is associated with chronic immune activation, PD-1 may contribute to age-associated T-cell dysfunction. Our data showed the following results in aged mice: (i) the number of PD-1-expressing T cells and the level of expression of PD-Ls was increased on dendritic cell subsets and T cells; (ii) PD-1( ) T cells were exhausted effector memory T cells, as shown by their lower level of CD127, CD25 and CD28, as well as their limited proliferative and cytokine-producing capacity; (iii) the expression of PD-1 was up-regulated after T-cell receptor-mediated activation of CD8( ) T cells, but not of CD4( ) T cells; (iv) blockade of the PD-1/PD-L1 pathway moderately improved the cytokine production of T cells from old mice but did not restore their proliferation; and (v) blockade of the PD-1/PD-L1 pathway did not restore function of PD-1( ) T cells; its effect appeared to be exclusively mediated by increased functionality of the PD-1(-) T cells. Our data thus suggest that blockade of the PD-1/PD-L1 is not likely to be efficient at restoring exhausted T-cell responses in aged hosts, although improving the responses of PD-1(-) T cells may prove to be a helpful strategy in enhancing primary responses.
MeSH Terms
- Aging
- Animals
- Antigens, Surface
- Apoptosis Regulatory Proteins
- B7-1 Antigen
- B7-H1 Antigen
- Cell Proliferation
- Cytokines
- Flow Cytometry
- Membrane Glycoproteins
- Mice
- Mice, Inbred C57BL
- Peptides
- Programmed Cell Death 1 Receptor
- T-Lymphocytes
Invariant natural killer T (iNKT) cells are known to constitutively express the high affinity interleukin-2 receptor α chain (CD25) in neonates, but the functional consequence of this phenotype is unknown. Here, we show that high numbers of CD25-expressing iNKT cells are present early in gestation and represent a significant proportion of the developing immune system. Despite their activated phenotype, neonatal iNKT cells express high levels of the Krüppel-like factor-2, a transcription factor associated with quiescent T cells, and require de novo T-cell receptor and CD28 co-stimulation to proliferate. In contrast to bona fide CD4/CD25-expressing regulatory T cells, neonatal iNKT cells do not suppress T-cell responses, indicating that they do not represent an immunosuppressive cell subset. Evidence that neonatal iNKT cells respond to dramatically reduced amounts of CD1d-restricted antigen compared with adult iNKT cells or T cells, and that their proliferation can be induced in the absence of early interleukin-2 suggest that constitutive expression of CD25 'primes' neonatal iNKT cells to respond rapidly to low amounts of antigen. This unique phenotype, which is distinct from adult iNKT cells, as well as other CD25-expressing activated T or regulatory T cells, may be important to ensure stability of a structurally limited peripheral iNKT-cell repertoire early in life.
MeSH Terms
- Adult
- Aging
- Antibodies, Monoclonal
- Antigens
- Antigens, CD
- Antigens, Differentiation, T-Lymphocyte
- CD28 Antigens
- Cell Proliferation
- Female
- Fetal Blood
- Forkhead Transcription Factors
- Gene Expression
- Humans
- Immune Tolerance
- Infant, Newborn
- Interleukin-2
- Interleukin-2 Receptor alpha Subunit
- Interleukin-7 Receptor alpha Subunit
- Kruppel-Like Transcription Factors
- L-Selectin
- Labor, Obstetric
- Lectins, C-Type
- Leukocyte Common Antigens
- Lymphocyte Activation
- Lymphocyte Count
- Male
- Natural Killer T-Cells
- Pregnancy
- Receptors, Antigen, T-Cell
- T-Lymphocytes
Cytokine generation by T cells and monocytes was determined for 50 subjects aged 65 yr or older and concurrently studied young subjects individually matched to each old subject for sex, race, and national origin. Highly significant differences between cytokine levels of old and young subjects all were gender specific. For T cells stimulated with anti-CD3 plus anti-CD28 antibodies, mean ratios of IFN-gamma generation for healthy old to young subjects were 0.22 for men (P<0.001; n=15) and 3.35 for women (P<0.001; n=13), and those of IL-17 were 0.30 for men (P<0.001) and no difference for women. CD8 T cells were the source of high IFN-gamma in healthy old women. For old men with an inflammatory or immune disease (n=10), mean old to young ratios of T-cell-generated IFN-gamma and IL-17 increased with disease severity up to 5.78 and 2.97 (both P<0.01), respectively, without changes for old women with similar diseases (n=12). For differentiated LPS-stimulated monocytes, old to young ratios of TNF-alpha and IL-6 generation were high only in women with immune or inflammatory disease (2.38, P<0.05 and 1.62, P<0.01, respectively), whereas ratios of IFN-gamma-evoked IP-10 chemokine were low in all groups. Alterations in immune cytokine profiles with aging show significant gender specificity.
MeSH Terms
- Aged
- Aged, 80 and over
- Aging
- Cytokines
- Enzyme-Linked Immunosorbent Assay
- Female
- Flow Cytometry
- Humans
- Interferon-gamma
- Interleukin-17
- Interleukin-6
- Male
- Monocytes
- Sex Factors
- T-Lymphocytes
- Tumor Necrosis Factor-alpha
T cell responses are compromised in the elderly. The B7-CD28 family receptors are critical in the regulation of immune responses. We evaluated whether the B7-family and CD28-family receptors were differentially expressed in dendritic cells, macrophages, and CD4( ) and CD8( ) T cells from young and old mice, which could contribute to the immune dysfunction in the old. Although most of the receptors were equally expressed in all cells, >85% of the old naive CD8( ) T cells expressed B7-H1 compared with 25% in the young. Considering that B7-H1 negatively regulates immune responses, we hypothesized that expression of B7-H1 would downregulate the function of old CD8( ) T cells. Old CD8( ) T cells showed reduced ability to proliferate, but blockade of B7-H1 restored the proliferative capacity of old CD8( ) T cells to a level similar to young CD8( ) T cells. In vivo blockade of B7-H1 restored antitumor responses against the B7-H1(-) BM-185-enhanced GFP tumor, such that old animals responded with the same efficiency as young mice. Our data also indicate that old CD8( ) T cells express lower levels of TCR compared with young CD8( ) T cells. However, following antigenic stimulation in the presence of B7-H1 blockade, the levels of TCR expression were restored in old CD8( ) T cells, which correlated with stronger T cell activation. These studies demonstrated that expression of B7-H1 in old CD8( ) T cells impairs the proper activation of these cells and that blockade of B7-H1 could be critical to optimally stimulate a CD8 T cell response in the old.
MeSH Terms
- Aging
- Animals
- Antigens, Surface
- Apoptosis Regulatory Proteins
- B7-1 Antigen
- B7-H1 Antigen
- CD28 Antigens
- CD8-Positive T-Lymphocytes
- Cell Communication
- Cell Division
- Cell Line, Tumor
- Cell Proliferation
- Cellular Senescence
- Down-Regulation
- Lymphocyte Activation
- Lymphocyte Count
- Macrophages
- Membrane Glycoproteins
- Mice
- Mice, Inbred BALB C
- Neoplasms, Experimental
- Peptides
- Programmed Cell Death 1 Receptor
Age-related changes of gene expression contribute to the physiological alteration observed with human ageing. Herein, the abundance of a selection of 148 transcripts involved in immunosenescence and stress response was compared in total RNA of PBMC of healthy young to middle-age probands (35.0 /- 6.5 year old) and healthy old probands (82.5 /- 6.8 year old). This study provides a list of 16 differentially abundant transcripts species in the healthy old probands. Thus, these changes of abundance can be considered as easily accessible biomarkers of ageing. Some of these differential abundances like CD28, CD69, LCK (decreased abundance in old subjects), CD86, Cathepsin D, H and S (increased abundance in old subjects) might explain biochemical and cytochemical changes observed at the protein level in the immune system and thus might correspond to regulatory processes affecting the ageing process. Indeed these changes reflect the low-grade pro-inflammatory status observed in old persons and suggest a hypo-responsiveness of T-cells together with an increase in antigen presentation potential. In addition, among the differentially abundant transcripts were transcripts involved in the oxidative stress response HMOX1 and HSPA6 mRNAs were found as more abundant in PBMC from elderly subjects.
MeSH Terms
- Adult
- Aged
- Aged, 80 and over
- Aging
- Antigen Presentation
- Biomarkers
- Gene Expression Profiling
- Humans
- Leukocytes, Mononuclear
- Oligonucleotide Array Sequence Analysis
- Oxidative Stress
- RNA, Messenger
Chronic obstructive pulmonary disease (COPD) is a chronic inflammatory disease of the lungs that usually manifests late in life. Physiologic and immunologic changes that occur in COPD often mimic changes seen in the aging lung. This has led some to characterize COPD as an "accelerated aging phenotype." At the molecular level, COPD and aging share common mechanisms and are associated with significant dysregulation of the immune systems. Aging and COPD are characterized by increases in proinflammatory cytokines such as interleukin (IL)-6 and tumor necrosis factor (TNF)-alpha, which are implicated in aging-related inflammatory diseases and correlate with degree of obstruction in COPD. There is an age-dependent decline in naïve T cells with oligoclonal expansion of CD8( ) CD28(null) T cells from chronic antigenic stimulation. The increase in CD8( ) CD28 (null) T regulatory cells inhibits antigen-specific CD4( ) T cell responses, leading to a decline in adaptive immune response. To compensate for the decline in the adaptive immune function there is a paradoxical up-regulation of innate immune system resulting in a proinflammatory state. The dysregulated adaptive immune system with activated innate immune responses seen with aging results in recruitment and retention of neutrophils, macrophages, and CD4( ) and CD8( ) T cells in the lungs of smokers with COPD. Once the inflammation is triggered, there is a self-perpetuating cascade of inflammation and lung parenchymal damage. This review will focus on how the aging immune system may contribute to COPD development later in life in susceptible individuals.
MeSH Terms
- Aging
- Humans
- Immunity
- Interleukin-6
- Pulmonary Disease, Chronic Obstructive
- Tumor Necrosis Factor-alpha
An age-related decline in human immune response is marked by the accumulation of CD28(-) CD8 T cells, which is attributed to repeated antigenic stimulation and to homeostatic proliferation mediated by cytokines such as IL-15. However, the identity of the cytokines that are responsible for the maintenance of CD28 expression is less known. Here, we report the role of IL-21 in the regulation of IL-15-mediated growth and CD28 expression of CD8 memory T cells of young and old donors. We showed that IL-21 drives more IL-15-stimulated cells to enter cell division and to undergo apoptosis. Furthermore, IL-21 preferentially enhanced IL-15-induced proliferation of CD28( ) CD8 memory T cells over their CD28(-) counterparts, as CD28( ) cells expressed higher levels of IL-15R and IL-21R and greater pSTAT5 upon IL-15 and IL-21 stimulation. In addition, IL-21 reduced IL-15-induced CD28 down-regulation in CD8 memory T cells. Finally, the ability of proliferation and survival in response to homeostatic cytokines IL-15 and IL-21 of CD28( ) CD8 memory T cells was well-maintained with age. Together, these findings suggest that IL-21 enhances IL-15-mediated proliferation of CD8 memory T cells, particularly CD28( ) memory T cells, and also serves as an antagonist to the IL-15-induced increase of CD28(-) CD8 T cells.
MeSH Terms
- Adult
- Aged
- Aged, 80 and over
- Aging
- Apoptosis
- CD28 Antigens
- CD8-Positive T-Lymphocytes
- Cell Division
- Cells, Cultured
- Homeostasis
- Humans
- Immunologic Memory
- Interleukin-15
- Interleukins
- RNA, Messenger
- Receptors, Interleukin-15
- STAT3 Transcription Factor
- STAT5 Transcription Factor
- Signal Transduction
- T-Lymphocyte Subsets
The purpose of this study was to investigate the modulation of selected cell surface markers and proinflammatory cytokines production in relation to ageing, and cigarette smoking. The analysis of cell surface receptors was performed by the flow cytometry and cytokines levels were evaluated by the sandwich enzyme immunoassays. We found a decreased expression of CD69, CD28, CD11b, CD95 markers in old population compared to young people (p<0.05; p<0.001). The memory CD45RO lymphocytes were markedly expanded in older population in comparison to young donors (12.93 /-5.92 %, p<0.001) and the selectin CD62L was significantly increased on granulocytes in aged people (p<0.05). Our findings demonstrated an augmented level of CD3 and CD28 on lymphocytes in smokers (p<0.05; p<0.005). The significant depression of CD16 56 molecule was recorded in smokers (10.86 /-0.80%) when compared to non-smokers (14.44 /-0.46; p<0.05). Our results showed a significantly diminished levels of interleukin (IL)-1beta (1.93 /-0.48 pg/ml), and increased levels of IL-6 and tumor necrosis factor (TNF)-alpha in elderly population compared to young people (p<0.05; p<0.001). The present data support previous suggestions that senescence and cigarette smoking may contribute to changes in the immune system activity, resulting in altered cell surface marker expression and cytokine levels (Tab. 1, Fig. 3, Ref. 81). Full Text (Free, PDF) www.bmj.sk.
MeSH Terms
- Adult
- Aged
- Aging
- Antigens, CD
- Cytokines
- Humans
- Interleukin-1beta
- Interleukin-6
- Middle Aged
- Smoking
- Tumor Necrosis Factor-alpha
- Young Adult
Scurfy (Sf) mice lack CD4( )Foxp3( ) regulatory T cells and develop fatal multiorgan inflammation (MOI) mediated by CD4( ) T cells. Introducing Il2(-/-) gene into Sf mice (Sf.Il2(-/-)) inhibited inflammation in skin and lung. As a major integrin receptor for the organs, we compared CD103 expression on the CD4( ) T cells of B6, Il2(-/-), Sf, and Sf.Il2(-/-) mice. CD103( )CD4( ) T cells, but not CD8( ) T cells or CD11c( ) dendritic cells, were significantly up-regulated only in Sf mice, indicating Il2(-/-) dominantly and specifically inhibited CD103 up-regulation in Sf CD4( ) T cells. In addition, CD4( )Foxp3( ) regulatory T cell CD103 expression was not reduced in Il2(-/-) mice. Introducing CD103(-/-) into Sf mice inhibited inflammation in skin and lung as compared with age-matched Sf mice, but they died at approximately 7 wk old with inflammation developed in skin, lungs, and colon, demonstrating fatal MOI induced by CD103-independent mechanism. Transfer of Sf CD4( ) T cells induced MOI more rapidly than CD103(-)CD4( ) T cells, indicating the presence of CD103-dependent mechanism for inflammation. In vitro stimulation with anti-CD3 plus anti-CD28 beads confirmed that CD103 induction in the CD4( )Foxp3(-) T cells in Il2(-/-) and Sf.Il2(-/-) is defective and cannot be restored by rIL-2 or rIL-15. The data indicate that IL-2 is required for optimal CD103 induction on CD4( ) T cells in Sf mice and this effect contributes to inflammation in an organ-specific manner. IL-2 also has additional roles because the protection of skin and lung inflammation in Sf.Il2(-/-), but not Sf.CD103(-/-) mice is lifelong and Sf.Il2(-/-) mice have longer lifespan than Sf.CD103(-/-) mice.
MeSH Terms
- Animals
- Antigens, CD
- CD4-Positive T-Lymphocytes
- Cause of Death
- Inflammation
- Integrin alpha Chains
- Interleukin-2
- Longevity
- Lung
- Mice
- Mice, Inbred Strains
- Mice, Mutant Strains
- Skin
- T-Lymphocytes, Regulatory
- Transcriptional Activation
The accumulation of CD28(-) T cells, particularly within the CD8 subset, is one of the most prominent changes during T-cell homeostasis and function associated with aging in humans. CD28, a major co-stimulatory receptor, is responsible for the optimal antigen-mediated T-cell activation, proliferation and survival of T cells. CD28(-) T cells exhibit reduced antigen receptor diversity, defective antigen-induced proliferation and a shorter replicative lifespan while showing enhanced cytotoxicity and regulatory functions. Gene expression analyses reveal profound changes of CD28(-) T cells in comparison to their CD28( ) counterparts and corroborate their functional differences. Here we review recent advances in our understanding of CD28(-) T cells and their role in the age-associated decline of immune function.
MeSH Terms
- Aging
- Animals
- CD28 Antigens
- CD4-Positive T-Lymphocytes
- CD8-Positive T-Lymphocytes
- Cell Adhesion Molecules
- Cytokines
- Humans
- Interferons
- Receptors, Cytokine
- Receptors, Natural Killer Cell
To explore whether any co-stimulatory receptor(s) for TCR signaling is involved in the age-associated decline in T-cell function, we analyzed changes in these receptors in freshly isolated mouse CD4( ) T cells during aging. Both the mRNA and protein expression levels of CTLA-4 and PD-1, negative co-stimulatory receptors, increase with aging. No such changes are observed for CD28, a positive regulatory receptor. PD-1 is highly expressed on the surface of old, but not young, mouse T cells, while the level of surface-expressed CTLA-4 is very low regardless of age. PD-1 is preferentially expressed on the surface of effector-memory (CD44(hi)CD62L(lo)) T cells, a subset that increases with aging. CD4( )PD-1( ) T cells from old mice exhibit proliferative hyporesponsiveness. These results suggest that the up-regulation of surface-expressed PD-1 may cause the age-dependent functional decline in effector-memory T cells.
MeSH Terms
- Aging
- Animals
- Antigens, Surface
- Apoptosis Regulatory Proteins
- Blotting, Western
- Immunologic Memory
- Male
- Mice
- Mice, Inbred C57BL
- Phenotype
- Programmed Cell Death 1 Receptor
- T-Lymphocytes, Regulatory
- Up-Regulation
Supplemental vitamin E alleviates age-related defects in interleukin (IL)-2 production, T cell proliferation, and immune synapse formation. Here, we evaluated the effect of in vitro supplementation with 46 mumol/L of vitamin E on T cell receptor-proximal signaling events of CD4( ) T cells from young (4-6 mo) and old (22-26 mo) C57BL mice. Aged murine CD4( ) T cells stimulated via CD3 and CD28, tyrosine 191 of the adaptor protein Linker for Activation of T cells (LAT), was hypo-phosphorylated. Supplementation with vitamin E eliminated this difference in the tyrosine phosphorylation of LAT. By using a flow cytometric assay, the age-related differences in the activation-induced phosphorylation of LAT were observed in both naïve and memory T cell subsets. In addition, supplementation with vitamin E eliminates the age-related differences in LAT phosphorylation in both T cell subsets. Neither age nor vitamin E supplementation altered the fraction of LAT entering the membrane compartment. Furthermore, neither age nor vitamin E influenced the phosphorylation of Lck and Zap70, indicating that associated changes in LAT phosphorylation were not caused by alterations in activation states of the upstream kinases Lck and Zap70.
MeSH Terms
- Adaptor Proteins, Signal Transducing
- Aging
- Animals
- CD4-Positive T-Lymphocytes
- Cells, Cultured
- Lymphocyte Activation
- Lymphocyte Specific Protein Tyrosine Kinase p56(lck)
- Membrane Proteins
- Mice
- Mice, Inbred C57BL
- Phosphoproteins
- Phosphorylation
- Specific Pathogen-Free Organisms
- Spleen
- Vitamin E
- ZAP-70 Protein-Tyrosine Kinase
The activation and expansion of naïve T cells require costimulatory signals provided by CD28 and TNF family members. In contrast, for many years it was believed that memory T cells do not require CD28 costimulation for expansion during secondary responses. This was based on in vitro experiments that suggested the re-activation of memory T cells is somewhat independent of costimulation. Recent in vivo evidence, however, has challenged this and shown that both CD4 and CD8 memory T cells require CD28 costimulation for maximal expansion and pathogen clearance. This requirement has important implications for host immunity, vaccine development and immunotherapeutics.
MeSH Terms
- Aging
- Animals
- Autoimmune Diseases
- CD28 Antigens
- Cell Differentiation
- Graft Rejection
- Humans
- Immunologic Memory
- Infections
- Lymphocyte Activation
- Neoplasms
- Receptor Cross-Talk
- Signal Transduction
- T-Lymphocytes
- Tumor Necrosis Factors
CD28 molecule expression on the surface of T cells plays a critical role in upregulation of various cytokines synthesis and T-helper (Th) cell proliferation and differentiation. However aging induces a decrease in CD28 expression and unbalance of Th1/Th2, leading to impairment of Th-cell mediated immune function. The purpose of this study was to assess the effects of moderate exercise training on CD28 expression and the balance of Th1/Th2 cells in elderly people. Forty-eight elderly subjects were assigned to an exercise training group (EXC: 13 males, 15 females; aged 61-76) or a non-exercise control group (CON: 7 males, 13 females; aged 62-79). Subjects in EXC participated in exercise sessions 5-days a week for 6 months. Meanwhile, subjects in CON maintained their normal physical activity levels during the study period. Blood samples were collected before and after the training period. Samples were measured for the number of leukocytes and lymphocytes, as well as for CD3 , CD4 , CD28 CD4 , IFN-gamma CD4 , IL-4 CD4 cells. The number of leukocytes, lymphocytes, and CD3 cells did not change after 6 months in both EXC and CON. The number of CD4 and CD28 CD4 cells significantly increased after the training in EXC (P < 0.05), while CON did not show significant changes. In the EXC group, IFN-gamma CD4 cell numbers were significantly higher following the training (P < 0.05), but the number of IL-4 CD4 cells was not changed. In the CON group, there were no significant alterations in IFN-gamma CD4 and IL-4 CD4 cell numbers. In conclusion, moderate exercise training in the elderly is associated with improvement of expression of CD28 on Th cells and Th1/Th2 balances. Therefore, exercise training could up-regulate Th cell-mediated immune functions and be helpful for a decrease in the risk of infections and autoimmune diseases in elderly people.
MeSH Terms
- Aged
- Aging
- CD28 Antigens
- Cell Differentiation
- Cell Separation
- Exercise
- Female
- Flow Cytometry
- Humans
- Interferon-gamma
- Interleukin-4
- Lymphocyte Activation
- Male
- Middle Aged
- Motor Activity
- Physical Endurance
- Th1 Cells
- Th2 Cells
To determine if untreated HIV-1 infection and progression is associated with premature aging of memory CD8 and CD4 T cells and naive CD4 T cells. Twenty HIV-1-infected fast progressors and 40 slow progressors were included in our study, using risk set sampling. The expression of cell surface markers reflecting the differentiation stages of lymphocytes was measured using flow cytometry analyses performed on cryopreserved peripheral blood mononuclear cells. We found that HIV-1 disease progression is associated with a decreased CD28 median florescence intensity on CD4 and CD8 T cells; an increased proportion of intermediate- and late-differentiated CD8 T cells and a decreased CD31 median florescence intensity on naive CD4 T cells of recent thymic origin. A selective depletion of peripherally expanded naive CD4 T cells was found to be associated with HIV-1 infection but not with HIV-1 disease progression. The overall change during HIV-1 infection and progression is associated with a shift in the T-cell population toward an aged conformation, which may be further compromised by impaired renewal of the less-differentiated CD4 T-cell population. Our results suggest that HIV-1 infection induces an accelerated aging of T lymphocytes, which is associated with the clinical progression to AIDS and death.
MeSH Terms
- Aging
- CD4-Positive T-Lymphocytes
- CD8-Positive T-Lymphocytes
- Case-Control Studies
- Cohort Studies
- Disease Progression
- HIV Infections
- HIV-1
- Humans
- Immunologic Memory
- Male
- T-Lymphocytes
The goal of this study was to investigate the role of the adipokine adiponectin (APN) in development of spontaneous colitis in IL-10 knockout (KO) mice. To this aim, we generated double IL-10 APN KO mice and compared their disease development to that of single IL-10 KO mice. Both IL-10 KO and double IL-10 APN KO mice spontaneously developed colitis of comparable severity. No significant differences in inflammatory infiltrate or crypt elongation were observed in colonic tissue obtained from IL-10 KO and double IL-10 APN KO mice at either 12 or 20 wk of age. A comparable increase in circulating levels of serum amyloid A and IFN-gamma was observed in IL-10 KO and double IL-10 APN KO mice as disease progressed. In vitro stimulation of lymphocytes from mesenteric lymph nodes with anti-CD3 and anti-CD28 induced a significantly higher production of IL-17 and TNF-alpha in IL-10 KO and double IL-10 APN KO mice compared with their healthy littermates. No significant differences in cytokine production from lymphocytes or colonic mRNA expression of cytokines were observed between IL-10 KO and double IL-10 APN KO mice. Both IL-10 KO and double IL-10 APN KO mice had a similar decrease in body weight and bone mass compared with their respective healthy littermates. Finally, APN deficiency did not lead to development of insulin resistance, either in APN KO or double IL-10 APN KO mice. In conclusion, lack of APN does not play a significant role in the pathogenesis of spontaneous colonic inflammation in the IL-10 KO model.
MeSH Terms
- Adiponectin
- Age Factors
- Aging
- Animals
- Blood Glucose
- Body Weight
- Bone Density
- Cells, Cultured
- Colitis
- Disease Progression
- Inflammation Mediators
- Insulin
- Insulin Resistance
- Interferon-gamma
- Interleukin-10
- Interleukin-17
- Leptin
- Lymphocyte Activation
- Lymphocytes
- Mice
- Mice, Inbred C57BL
- Mice, Knockout
- RNA, Messenger
- Serum Amyloid A Protein
- Severity of Illness Index
- Tumor Necrosis Factor-alpha
Inhibitory receptors of the CD28 family, CTLA-4 and PD-1 deliver negative signals that regulate the balance between T cell activation, tolerance, and immunopathology. Manipulation of these pathways has been utilized by pathogens and tumors to establish chronic infections or to promote tumor survival. In this review, we examine the role of CTLA-4 and PD-1 in regulating immune response and discuss their therapeutic potential during aging.
MeSH Terms
- Aging
- Animals
- Antigens, CD
- Apoptosis Regulatory Proteins
- CTLA-4 Antigen
- Communicable Diseases
- Drug Delivery Systems
- Humans
- Immune System
- Neoplasms
- Programmed Cell Death 1 Receptor
- T-Lymphocytes
Cell stress responses are ubiquitous in all organisms and are characterized by the induced synthesis of heat shock proteins (Hsp). Previous studies as well as recent reports by our group have consistently suggested that aging leads to an increase in the basal levels of Hsp70. Here we extend these studies by examining the differential Hsp70 response of peripheral blood lymphocyte (PBL) subsets. It is well established that with aging, one of the major changes in the T cell pool is an expansion of T cells with the memory phenotype as well as those deficient for the CD28 molecule. To determine if alterations in the frequency of T cell subsets might be responsible for the observations, we have carried out a more comprehensive flow cytometric analysis of the various phenotypes of PBL under unstimulated conditions. Cells were obtained from 10 young and 10 elderly normal subjects. The basal Hsp70 levels in the various PBL phenotypes were comparable between young and elderly subjects. However, different patterns of Hsp70 response were noticed among the PBL subtypes, which were similar in both young and elderly subjects. In particular, the memory cell phenotypes produced more Hsp70 than the naïve phenotypes. These results suggest that aging-related changes in basal Hsp70 levels in PBL are linked to the altered frequency of lymphocyte subsets and not to increases in aged lymphocytes per se. In addition, the increase in Hsp70 can be interpreted as the result of a tendency towards more pronounced cellular differentiation in aging.
MeSH Terms
- Adult
- Aged
- Aged, 80 and over
- Aging
- CD28 Antigens
- CD4-Positive T-Lymphocytes
- CD8-Positive T-Lymphocytes
- Female
- HSP70 Heat-Shock Proteins
- Humans
- Lymphocyte Subsets
- Male
Senescent T-lymphocytes are antigen-experienced cells that express the killer-cell lectin-like receptor G1 (KLRG1) and/or CD57; fail to clonally expand following further antigenic stimulation and prevail in the resting blood of older adults compared to the young. Physical exercise mobilises T-lymphocytes into the bloodstream and is therefore a model with which to compare age-related phenotypes of blood-resident T-cells with those T-cells entering the blood from peripheral lymphoid compartments. Eight young (Y; Age: 21 /-3 years) and 8 older (O; Age: 56 /-3 years) healthy males completed a maximal treadmill exercise protocol. Blood lymphocytes isolated before, immediately after and 1h after exercise were assessed for cell surface expression of KLRG1, CD57, CD28, CD45RA, CD45RO, CD62L and lymphocyte subset markers using three-colour flow cytometry. Lymphocyte subset numbers (CD3 , CD3 /CD4 , CD3 /CD8 and CD3-/CD56 ) increased with exercise (p<0.05) but were not different between Y and O. At rest and immediately after exercise, the percentage of CD3 /CD8 T-lymphocytes expressing KLRG1 and CD45RO was greater in O than Y, whereas Y had a greater expression of CD45RA and CD62L than O. The percentage of all CD3 /CD8 and CD3 /CD4 T-lymphocytes expressing KLRG1 and CD57 increased after exercise, but the magnitude of change was not age-dependent. In conclusion, there is a greater proportion of senescent CD3 /CD8 T-lymphocytes in the blood of older adults compared to young at rest and immediately after exhaustive exercise, indicating that the greater frequency of KLRG1 /CD8 T-lymphocytes in older humans is ubiquitous and not localised to the peripheral blood.
MeSH Terms
- Adult
- Aging
- CD28 Antigens
- CD57 Antigens
- Cell Movement
- Cellular Senescence
- Exercise
- Flow Cytometry
- Humans
- Immunophenotyping
- Lectins, C-Type
- Male
- Middle Aged
- Physical Endurance
- Receptors, Immunologic
- T-Lymphocytes
- Trans-Activators
We used transgenic mice to investigate the effect of IL-2 stimulation on T lymphocyte functions of GILZ-overexpressing splenic T cells. When compared to their controls, T cells from transgenic mice underwent normal activation after stimulation with anti-CD3 plus anti-CD28 monoclonal antibodies, as evaluated by CD25 expression, CD2 up-regulation and proliferation. IL-10, IL-13 and IFN-gamma increased more consistently in CD3/CD28-triggered TG compared to WT splenic CD4( )cells. Analysis of the CD4( )and CD8( )T cells demonstrated a decreased CD4( )/CD8( )T-cell ratio (1:1 instead of 1:2) in response to IL-2 stimulation, possibly due to an unresponsiveness of IL-2 receptor beta and/or gamma chains. Finally, the total number of T cells was significantly increased in aged mice and this was due to the augmentation of CD4( )T cells. These results support the hypothesis that GILZ regulates, at least in part, peripheral T-cell functions by influencing their responsiveness to IL-2.
MeSH Terms
- Aging
- Animals
- CD4-Positive T-Lymphocytes
- CD8-Positive T-Lymphocytes
- Cytokines
- Enzyme-Linked Immunosorbent Assay
- Flow Cytometry
- Interleukin-2
- Lymphocyte Activation
- Mice
- Mice, Transgenic
- Spleen
- Transcription Factors
Recent observations indicate that immunosenescence is not accompanied by an unavoidable and progressive deterioration of the immune function, but is rather the result of a remodeling where some functions are reduced, others remain unchanged or even increased. In addition, it appears that the ancestral/innate compartment of the immune system is relatively preserved during aging in comparison to the more recent and sophisticated adaptive compartment that exhibit more profound modifications. The T-cell branch displays an age-dependent decline of the absolute number of total T-cells (CD3 ), involving both CD4 and CD8 subsets, accompanied by an increase of NK cells with well-preserved cytotoxic function and by a reduction of B-cells. One of the main characteristics of the immune system during aging is a progressive, age-dependent decline of the virgin T-cells (CD95-), which is particularly profound at the level of the CD8 subpopulation of the oldest old subjects. The progressive exhaustion of this important T-cell subpopulation dedicated primarily to the defense against new antigenic challenges (viral, neoplastic, bacterial ones), could be a consequence of both the thymic involution and the lifelong chronic antigenic stimulation. The immune function of the elderly, is therefore weakened by the exhaustion of CD95- virgin cells that are replaced by large clonal expansions of CD28- T-cells. The origin of CD28- cells has not been completely clarified yet, but it is assumed that they represent cells in the phase of replicative senescence characterized by shortening telomers and reduced proliferative capacity. A major characteristic of the immune system during aging is the up-regulation of the inflammatory responses which appears to be detrimental for longevity. In this regard, we have recently observed a progressive age-dependent increase of type 1(IL-2, IFN-gamma, TNF-alpha) and type 2 (IL-4, IL-6, IL-10) positive CD8 T-cells; in particular, type 1 cytokine-positive cells significantly increased, with age, in all CD8 subsets particularly among effector/cytotoxic and memory cells. A major force able to drive a chronic pro-inflammatory state during aging may be represented by persistent viral infections by EBV and CMV. Therefore, we have determined the frequency and the absolute number of viral antigen-specific CD8 T-cells in subjects older than 85 years, who were serologically positive for CMV or EBV. In the majority of these subjects we detected the presence of T lymphocytes positive for epitopes of CMV or EBV. In all subjects the absolute number of CMV-positive CD8 cells outnumbered that of EBV-positive ones. In addition, the majority of CMV T cells were included within the CD28- subpopulation, while EBV T cells belonged mainly to the CD28 subset. These data indicate that the chronic antigenic stimulation induced by persistent viral infections during aging bring about important modifications among CD8 subsets, which are particularly evident in the presence of CMV persistence. The age-dependent expansions of CD8 CD28- T-cells, mostly positive for pro-inflammatory cytokines and including the majority of CMV-epitope-specific cells, underlines the importance of chronic antigenic stimulation in the pathogenesis of the main immunological alterations of aging and may favour the appearance of several pathologies (arteriosclerosis, dementia, osteoporosis, cancer) all of which share an inflammatory pathogenesis.
MeSH Terms
- Aged, 80 and over
- CD8-Positive T-Lymphocytes
- Cytokines
- Female
- Humans
- Immune System
- Immunologic Memory
- Inflammation
- Longevity
- Lymphocyte Activation
- Male
Natural regulatory CD4( ) CD25( ) T cells play an important role in preventing autoimmunity by maintaining self-tolerance. They express CD25 constitutively and are produced in the thymus as a functionally mature T-cell population. Changes in the potential of these cells to regulate the activity of conventional effector lymphocytes may contribute to an increased susceptibility to infection, cancer and age-associated autoimmune diseases. In this study we demonstrated that the thymi of aged mice are populated by a higher percentage of CD4( ) CD25( ) thymocytes than in young animals. The expression of several surface markers (CD69, CD5, CD28, CTLA-4, CD122, FOXP3), usually used to characterize the phenotype of CD4( ) CD25( ) T regulatory cells, was compared between young and aged mice. We also examined the ability of sorted thymus-deriving regulatory T cells of young and aged BALB/c mice to inhibit the proliferation of lymph node lymphocytes activated in vitro. Natural regulatory T cells isolated from the thymi of young mice suppress the proliferation of responder lymph node cells. We demonstrated that thymus-deriving CD4( ) CD25( ) T cells of old mice maintain their potential to suppress the proliferation of activated responder lymphocytes of young mice. However, their potential to inhibit the proliferation of old responder T cells is abrogated. Differences in the occurrence and activity of CD4( ) CD25( ) thymocytes between young and old animals are discussed in relation to the expression of these surface markers.
MeSH Terms
- Aging
- Animals
- Cell Proliferation
- Cells, Cultured
- Female
- Immunophenotyping
- Interleukin-2 Receptor alpha Subunit
- Mice
- Mice, Inbred BALB C
- Self Tolerance
- T-Lymphocyte Subsets
- T-Lymphocytes, Regulatory
- Thymus Gland
Aging is associated with an alteration of the immune response called immunosenescence. It is now well accepted that all parts of the immune system, the adaptive as well as the innate, undergo immunosenescence. However, the adaptive immune response and especially T cell functions are the most affected by aging. Aging is associated with profound changes in lymphocytes subpopulations, however, the functional changes within these subsets are more important to elucidate. Indeed, T cells present functional modifications resulting in a decreased clonal expansion and interleukin-2 (IL-2) production. So there should be an alteration in the activation process of T cells with aging involving the T cell receptor (TCR) and CD28 receptor signaling cascades. The alterations in membrane rafts composition and function can underline this altered activation of T cells with aging and then contribute to human immunosenescence. The experimental data in favor of this hypothesis will be reviewed.
MeSH Terms
- Aging
- Antigens
- CD28 Antigens
- Cell Membrane
- Cholesterol
- Cytoskeleton
- Humans
- Immune System
- Interleukin-2
- Lymphocyte Activation
- Membrane Microdomains
- Phosphoric Monoester Hydrolases
- Receptors, Antigen, T-Cell
- Signal Transduction
- T-Lymphocytes
Immune function in the elderly is associated with a number of phenotypic and functional abnormalities, and this phenomenon of immune senescence is associated with increased susceptibility to infection. The immune response to pathogens frequently declines with age, but the CD8( ) T-cell response to cytomegalovirus (CMV) is unusual, as it demonstrates a significant expansion over time. Here we have documented the CD4( ) T-cell immune response to CMV in healthy donors of different ages. The magnitude of the CMV-specific CD4( ) T-cell immune response increases from a mean of 2.2% of the CD4( ) T-cell pool in donors below 50 years of age to 4.7% in donors aged over 65 years. In addition, CMV-specific CD4( ) T cells in elderly donors demonstrate decreased production of interleukin-2 and less dependence on costimulation. CMV seropositivity is associated with marked changes in the phenotype of the overall CD4( ) T-cell repertoire in healthy aged donors, including an increase in CD57( ) expression and a decrease in CD28 and CD27 expression, a phenotypic profile characteristic of immune senescence. This memory inflation of CMV-specific CD4( ) T cells contributes to evidence that CMV infection may be damaging to immune function in elderly individuals.
MeSH Terms
- Aged
- Aging
- CD4-Positive T-Lymphocytes
- Cytomegalovirus
- Humans
- Interferon-gamma
- Interleukin-2
T cells deficient in CD28 expression have been implicated in the pathogenesis of rheumatoid arthritis (RA). Given that CD28-null T cells are functionally heterogeneous, we undertook this study to screen for novel receptors on these cells. Seventy-two patients with RA (ages 35-84 years) and 53 healthy persons (32 young controls ages 19-34 years, 21 older controls ages 39-86 years) were recruited. Phenotypes and proliferative capacity of T cells from fresh leukocytes and of long-term cultures were monitored by flow cytometry. Lung biopsy specimens from patients with RA-associated interstitial pneumonitis (IP) were examined by immunohistochemistry. Receptor functionality was assessed by crosslinking bioassays. Chronic stimulation of CD28( ) T cells in vitro yielded progenies that lacked CD28 but that gained CD56. Ex vivo analysis of leukocytes from patients with extraarticular RA showed a higher frequency of CD56( ),CD28-null T cells than in patients with disease confined to the joints or in healthy controls. CD56( ),CD28-null T cells had nil capacity for proliferation, consistent with cellular senescence. CD56( ) T cells had skewed T cell receptor (TCR) alpha/beta-chain usage and restricted TCR third complementarity-determining region spectra. Histologic studies showed that CD56( ) T cells were components of cellular infiltrates in RA-associated IP. CD56 crosslinking on T cells sufficiently induced cytokine production, although CD56/TCR coligation induced higher production levels. Chronic activation of T cells induces counterregulation of CD28 and CD56 expression. The loss of CD28 is accompanied by the gain of CD56 that confers TCR-independent and TCR-dependent activation pathways. We propose that accumulation of CD56( ) T cells in RA contributes to maladaptive immune responses and that CD56( ) T cells are potential targets for therapy.
MeSH Terms
- Adult
- Aged
- Aged, 80 and over
- Aging
- Arthritis, Rheumatoid
- Biopsy
- CD56 Antigen
- Cell Culture Techniques
- Female
- Flow Cytometry
- Humans
- Lung
- Lung Diseases, Interstitial
- Lymphocyte Activation
- Male
- Middle Aged
- T-Lymphocytes
Human CD4( ) T lymphocytes undergo aging-related changes leading to decreased immunity to infections and neoplasms, and to increased frequency of autoimmune diseases including rheumatoid arthritis (RA). Certain changes, observed in the CD4( ) cells of RA patients, resemble those observed during physiological aging, but occur at earlier age. Underlying cellular mechanism(s) of these similarities are so far largely unknown. Here we show that KLOTHO, a beta-glucuronidase gene whose activity changes are associated with aging phenotype, is down-regulated at the mRNA, protein, and enzymatic (beta-glucuronidase) activity levels both in the healthy elderly and especially in RA CD4( ) lymphocytes. Although the exact role of Klotho activity for CD4( ) cell function is unknown, we propose here that it might be involved in anti-inflammatory processes occurring in the young and healthy individuals, but reduced in both healthy elderly and RA patients. To support this hypothesis, we show here that the reduction of Klotho expression and activity in both elderly and patients' lymphocytes occurs in concert with the down-regulation of T cell costimulatory molecule CD28, the latter known to be dependent on increased levels of TNF-alpha. Thus, a common mechanism of KLOTHO down-regulation, but executed at various times in life, may underlie both physiological and disease-related T cell aging. Klotho activity might become a target of anti-RA drug development as well as a tool to help increase the immune system efficiency in the elderly.
MeSH Terms
- Adult
- Aged
- Aged, 80 and over
- Aging
- Arthritis, Rheumatoid
- CD28 Antigens
- CD4-Positive T-Lymphocytes
- Female
- Gene Expression Regulation
- Glucuronidase
- Health
- Humans
- Male
- Middle Aged
- Protein Binding
- Transcription, Genetic
Cells of the immune system are unique among normal somatic cells in that they have the capacity to upregulate the telomere-extending enzyme, telomerase, albeit in a precisely controlled fashion. Kinetic analysis of telomerase activity in long-term T cell cultures has documented that the high level of telomerase induced in concert with activation reaches a peak at 3-5 days, then declines by 3 weeks. The process is recapitulated during secondary antigenic stimulation, but by the third, and all subsequent stimulations in vitro, CD8 T cells are unable to upregulate telomerase. Cell division in the absence of telomerase activity results in progressive telomere shortening, and ultimately, the DNA damage/cell cycle arrest that is signaled by critically short telomeres. Cultures of senescent CD8 T cells show altered cytokine patterns, resistance to apoptosis, and absence of expression of the CD28 costimulatory receptor. CD8 T cells with these and other features of replicative senescence accumulate progressively with age, and at an accelerated rate, during chronic infection with HIV-1. Clinical studies have shown that high proportions of CD8 T cells with the senescent phenotype correlate with several deleterious physiologic outcomes, including poor vaccine responses, bone loss, and increased proinflammatory cytokines. CD8( )CD28(-) T cells have also been shown to exert suppressive activity on other immune cells. Based on the central role of telomere shortening in the replicative senescence program, we are developing several telomerase-based approaches as potential immunoenhancing treatments for aging and HIV disease. Gene therapy of HIV-specific CD8 T cells with the telomerase catalytic component (hTERT) results in enhanced proliferative capacity, increased anti-viral functions, and a delay in the loss of CD28 expression, with no changes in karyotype or growth kinetics. These proof-of-principle studies have led to screening for pharmacological approaches that might mimic the gene therapy effects, in a more clinically suitable formulation.
MeSH Terms
- Aging
- Antigens, CD
- CD28 Antigens
- CD8-Positive T-Lymphocytes
- Cell Division
- Cellular Senescence
- Humans
- Immune System Diseases
- Kinetics
- T-Lymphocytes
- Telomerase
Accumulation of CD28(null)CD8 T cells and the defects of these cells in response to antigenic stimulation are the hallmarks of age-associated decline of T cell function. However, the mechanism of these age-associated changes is not fully understood. In this study, we report an analysis of the growth of human CD28(null) and CD28 CD8 memory T cells in response to homeostatic cytokine IL-15 in vitro. We showed that 1) there was no proliferative defect of CD28(null)CD8 memory T cells in response to IL-15 compared with their CD28 counterparts; 2) stable loss of CD28 expression occurred in those actively dividing CD28 CD8 memory T cells responding to IL-15; 3) the loss of CD28 was in part mediated by TNF-alpha that was induced by IL-15; and 4) CCL4 (MIP-1beta), also induced by IL-15, had a significant inhibitory effect on the growth of CD28(null) cells, which in turn down-regulated their expression of CCL4 receptor CCR5. Together, these findings demonstrate that CD28(null)CD8 memory T cells proliferate normally in response to IL-15 and that IL-15 and its induced cytokines regulate the generation and growth of CD28(null)CD8 T cells, suggesting a possible role of IL-15 in the increase in CD28(null)CD8 T cells that occurs with aging.
MeSH Terms
- Aging
- CD28 Antigens
- CD8-Positive T-Lymphocytes
- Cell Proliferation
- Cytokines
- Humans
- Immunologic Memory
- Interleukin-15
- Reverse Transcriptase Polymerase Chain Reaction
T cells are vulnerable to age-associated changes. Vitamin E has been shown to improve T cell functions in the old. We studied gene expression profiles of T cells to better understand the underlying mechanisms of age and vitamin E-induced changes in T cell function. Young and old C57BL mice were fed diets containing 30 (control) or 500 (supplemented) ppm of vitamin E for 4 wks. Gene expression profiles of T cells were assessed using microarray analysis with/without anti-CD3/anti-CD28 stimulation. Genes associated with cytokines/chemokines, transcriptional regulation, signal transduction, cell cycle, and apoptosis were significantly up-regulated upon stimulation. Higher SOCS3 and lower growth factor independent 1 (Gfi-1) expression in old T cells may contribute to age-associated decline in proliferation. Higher Gadd45 and lower Bcl2 expression may contribute to increased apoptosis in old T cells. Vitamin E supplementation resulted in higher expression of genes involved in cell cycle regulation (Ccnb2, Cdc2, Cdc6) in old T cells. Vitamin E supplementation resulted in higher up-regulation of IL-2 expression in young and old T cells and lower up-regulation of IL-4 expression in old T cells following stimulation. These findings suggest that aging has significant effects on the expression of genes associated with signal transduction, transcriptional regulation, and apoptosis pathways in T cells, and vitamin E has a significant impact on the expression of genes associated with cell cycle and Th1/Th2 balance in old T cells. Further studies are needed to determine whether these changes are due to the effects of aging at a single-cell level or to the shift in the ratio of naïve:memory T cells with age.
MeSH Terms
- Age Factors
- Aging
- Animals
- Apoptosis
- Cell Cycle
- Gene Expression
- Gene Expression Profiling
- Genes, Immunoglobulin
- Lymphocyte Activation
- Male
- Mice
- Mice, Inbred C57BL
- Receptors, Antigen, T-Cell
- T-Lymphocytes
- Vitamin E
Immunosenescence is characterized by three main aspects: (i) the shrinkage of the T cell repertoire and the accumulation of oligoclonal expansions (megaclones) of memory/effector cells directed toward ubiquitary infectious agents; (ii) the involution of the thymus and the exhaustion of naïve T cells; and (iii) a chronic inflammatory status called inflamm-aging. We present here possible strategies to counteract these main aspects of immunosenescence in humans with particular attention to the reduction of antigenic load by pathogens, such as CMV, and the normalization of intestinal microflora, the possible utilization of IL-7 to reverse thymic involution, the purging of megaclones, the forced expression of CD28 on T lymphocytes, the reduction of inflamm-aging and the administration of nutrients such as vitamin D. Possible drawbacks of all these strategies are discussed. Finally, the complexity of a rejuvenation approach is stressed, with particular attention to the inhibitory role played by the "old microenvironment" on the performance of progenitor cells, the best candidate to counteract the decline in regenerative potential characteristic of organs and tissues from old organisms.
MeSH Terms
- Aging
- Antigens
- Biological Evolution
- Cytomegalovirus
- Cytomegalovirus Infections
- Humans
- Immune System
- Inflammation
- T-Lymphocytes
- Thymus Gland
Immunological changes associated with aging play a major role in both the blunted responses to infections as well as to vaccines intended to prevent many of these infections. Several independent studies on immune correlates of poor vaccine responsiveness have identified a novel immune biomarker of reduced antibody response to vaccination, namely high proportions of memory CD8 T lymphocytes lacking expression of the CD28 costimulatory molecule. Research on this population of CD8( )CD28(-) T lymphocytes has documented characteristics suggestive of replicative senescence, including inability to proliferate, reduced telomere length, and altered cytokine profiles. CD8( )CD28(-) T lymphocytes have also been associated with suppressor functions and with early mortality in the elderly. This article discusses some of the challenges involved in custom-designing vaccines for the elderly, and suggests several immunomodulatory strategies that may enhance vaccine responsiveness in this age group.
MeSH Terms
- Aging
- Animals
- Cell Proliferation
- T-Lymphocytes
- Vaccines
Invariant natural killer T (iNKT) cells represent a well-established T cell lineage characterised in humans by TCR consisting of an invariant alpha chain encoded by Valpha24-JalphaQ genes, paired preferentially with a Vbeta11 chain. iNKT cells also share some characteristics with NK cells, such as the expression of the NK-associated receptor CD161 in humans. The T cell immune response is the most dramatically affected by ageing, although age-associated alterations in the phenotype and function of other cells of the immune system have been demonstrated. Despite the importance of iNKT cells in the regulation of the immune response, there are a limited number of studies on the effect of ageing on peripheral blood iNKT cells. Thus, in this work we analyse the effect of ageing on peripheral blood Valpha24( )Vbeta11( ) iNKT cells by studying their frequency, phenotype and proliferative function in elderly individuals fulfilling the SENIEUR criteria of healthy ageing compared with healthy young donors. Our results demonstrated a significant decrease of the percentage of Valpha24( )Vbeta11( ) iNKT cells in elderly donors. No significant differences were found in the expression of CD27, CD28, CD45RO, CD45RA(bright), CD161, CD94 and NKG2D on iNKT cells from young and elderly individuals. Proliferation of Valpha24( )Vbeta11( ) iNKT cells in response to alpha-GalCer and IL2 was analysed by calculating the cumulative population doubling (PD) after 14 days of culture. The PD levels were lower in the elderly indicating that Valpha24( )Vbeta11( ) iNKT cells from healthy elderly subjects had an impaired proliferative capacity. These results indicate that ageing associates with a significant decline in the percentage and proliferative response of peripheral blood iNKT cells. Given the important immunoregulatory role of iNKT cells, these alterations in their number and function could contribute to the deleterious immune response in the elderly.
MeSH Terms
- Adult
- Age Factors
- Aged
- Aged, 80 and over
- Aging
- Antigens, CD
- Cell Lineage
- Cell Proliferation
- Cells, Cultured
- Cellular Senescence
- Galactosylceramides
- Humans
- Interleukin-2
- Killer Cells, Natural
- Lymphocyte Count
- Phenotype
- Receptors, Antigen, T-Cell, alpha-beta
- Reference Values
- T-Lymphocyte Subsets
Activation of naïve T cells requires synergistic signals produced by the T-cell receptor (TCR) and by CD28. We previously identified the novel adaptor ALX, which, upon overexpression in Jurkat T cells, inhibited activation of the interleukin-2 (IL-2) promoter by TCR/CD28, suggesting that it is a negative regulator of T-cell activation. To further understand the physiological role of ALX, ALX-deficient mice were generated. Purified T cells from ALX-deficient mice demonstrated increased IL-2 production, CD25 expression, and proliferation in response to TCR/CD28 stimulation. Enhanced IL-2 production and proliferation were also observed when ALX-deficient mice were primed in vivo with ovalbumin-complete Freund's adjuvant and then restimulated ex vivo. Consistent with our initial overexpression studies, these data demonstrate that ALX is a negative regulator of T-cell activation. While TCR/CD28-mediated activations of phosphotyrosine induction, extracellular signal-regulated kinase 1/2, Jun N-terminal protein kinase, IkappaB kinase alpha/beta, and Akt were unaltered, constitutive activation of p38 mitogen-activated protein kinase and its upstream regulators MKK3/6 were observed for ALX-deficient splenocytes. The phenotype of ALX-deficient mice resembled the phenotype of those deficient in the transmembrane adaptor LAX, and an association between ALX and LAX proteins was demonstrated. These results suggest that ALX, in association with LAX, negatively regulates T-cell activation through inhibition of p38.
MeSH Terms
- Adaptor Proteins, Signal Transducing
- Adaptor Proteins, Vesicular Transport
- Aging
- Animals
- Antibody Formation
- B-Lymphocytes
- Cell Death
- Cell Proliferation
- Down-Regulation
- Interleukin-2
- Lymphocyte Activation
- Membrane Proteins
- Mice
- Mice, Inbred C57BL
- Mice, Knockout
- Phosphoproteins
- Protein Binding
- Receptors, Interleukin-2
- Spleen
- Splenomegaly
- Staphylococcus
- Superantigens
- T-Lymphocytes
- p38 Mitogen-Activated Protein Kinases
Human cytomegalovirus (HCMV) is a ubiquitous beta-herpesvirus which persists lifelong after primary infection and can lead to a significant disease in the immunocompromised individuals. CD8( ) T cells are believed to play a crucial role in both the elimination of active infection and maintenance of HCMV latency. Large expansions of CD8( ) T cells specific for a single epitope of HCMV have been well documented in Caucasoid population. To date, no similar study has been performed in Chinese populations. Here we report the characteristics of HCMV-specific CD8( ) T cells in healthy young and elderly Chinese donors using pp65(495-503)-loaded HLA-A*0201 tetramers. Cells were stained with a combination of the tetramers and antibodies for CD28 and CD57 or a panel of TCR Vbeta and analyzed by three-color flow cytometry. The frequencies of pp65(495-503)-specific T cells within total CD8( ) T cell population were between 0.14 and 6.84% (mean 2.45%) in the young donors and were from 0.33 to 6.89% (mean 1.95%) in the elderly donors, respectively. There was no significant difference between the two groups. The expression of CD28 was decreased whereas CD57 expression was increased in tetramer-negative CD8( ) T cells in the elderly when compared with the young group. However, neither of these changes was found within tetramer-positive cell populations. Moreover, TCR Vbeta usage within tetramer-positive population was predominated by certain TCR Vbeta subsets. These results demonstrate that large expansions of HCMV-specific CD8( ) T cells with certain subsets TCR Vbeta exist both in the healthy young and in the elderly Chinese individuals, which may play a role in the maintenance of virus latency but have potential detrimental influence on the immune responses to other pathogens or vaccinations.
MeSH Terms
- Adult
- Aged
- Aged, 80 and over
- Aging
- Asian Continental Ancestry Group
- CD28 Antigens
- CD57 Antigens
- CD8-Positive T-Lymphocytes
- Cytomegalovirus
- Cytomegalovirus Infections
- Epitopes, T-Lymphocyte
- Female
- Flow Cytometry
- HLA-A2 Antigen
- Humans
- Male
- Phenotype
- Phosphoproteins
- Receptors, Antigen, T-Cell, alpha-beta
- T-Lymphocyte Subsets
- Viral Matrix Proteins
- Virus Latency
Recent studies on "nonthermal" effects of mobile phone radiofrequency (RF) suggest that RF can interact with cellular functions and molecular pathways. To study the possible RF effects on human lymphocyte activation, we analyzed CD25, CD95, CD28 molecules in unstimulated and stimulated CD4 e CD8 T cells in vitro. Peripheral blood mononuclear cells (PBMCs) from young and elderly donors were exposed or sham-exposed to RF (1,800 MHz, Specific Absorption Rate 2 W/kg) with or without mitogenic stimulation. No significant changes in the percentage of these cell subsets were found between exposed and sham-exposed lymphocytes in both young and elderly donors. Nevertheless, after RF exposure we observed a slight, but significant, downregulation of CD95 expression in stimulated CD4 T lymphocytes from elderly, but not from young donors. This age-related result is noteworthy given the importance of a such molecule in regulation of the immune response.
MeSH Terms
- Adult
- Aged, 80 and over
- Aging
- CD4-Positive T-Lymphocytes
- Cell Phone
- Cells, Cultured
- Gene Expression Regulation
- Humans
- Leukocytes, Mononuclear
- Lymphocyte Activation
- Radio Waves
- T-Lymphocytes, Helper-Inducer
- fas Receptor
The paper considers age-associated alterations of intracellular and intercellular cascades of transduction of proliferative, differentiating, pro- and antiapoptotic signals, their interaction and influence on proliferative activity, differentiation and apoptosis of the immune system cells. One of initial causes of these alterations is accumulation with age of a growing number of antigens exposed on the surface of antigen-presenting cells. As a result of chronic antigenic stimulation, caused by this factor, an insufficient quantity or a slowed down appearance of growth factor receptors (in particular, IL-2 receptor) and costimulation molecules, primarily CD28, on T-cells membrane is observed. Because of this proliferative and antiapoptotic signals, received by T-cells, have a smaller intensity that predetermine reduction of their proliferative activity, and also activity of telomerase, and a greater susceptibility to apoptosis. Permanent activation of immune system is also reflected in age-related increase of expression of CD95 and type I tumour necrosis factor receptor by lymphocytes (that aggravates their susceptibility to apoptosis), and in intensification of proinflammatory cytokine synthesis. The second main cause of alterations in the immune system is an age-related decrease in the synthesis of growth factors that are necessary for cell survival and proliferation. In particular, because of the lack of IL-7, apoptosis intensity of maturing T-cells increases in thymus. Thymic stromal cells remain without contact signals and growth factors generated by lymphocytes, and also undergo apoptosis that causes further reduction of T-lymphopoiesis. Similar events also occur in bone marrow that predetermines age-related decrease in B-lymphopoiesis and in telomerase activity of haemopoietic stem cells, and also their proliferative potential reduction.
MeSH Terms
- Aging
- Animals
- Antigen-Presenting Cells
- Antigens
- Apoptosis
- B-Lymphocytes
- Bone Marrow
- CD28 Antigens
- Cell Differentiation
- Cell Proliferation
- Hematopoietic Stem Cells
- Humans
- Interleukin-2
- Lymphocytes
- Receptors, Tumor Necrosis Factor, Type I
- Signal Transduction
- T-Lymphocytes
- Telomerase
- Thymus Gland
- fas Receptor
Several alterations in immune function and a concomitant progressive increase in pro-inflammatory status are the major characteristics of ageing process. Cytokines play a key role during ageing acting both in regulatory communication among cells and in effector activity during an immune response. The impact of age on intracellular Type 1 (IFN-gamma and TNF-alpha) and Type 2 (IL-4) cytokines, after stimulation with PMA/ionomycin, was determined in three CD4 T subsets, i.e. CD95- CD28 (virgin), CD95 CD28 (activated/memory), and CD95 CD28- (effector/memory) from 47 subjects aged between 21 and 99 years. The percentage of IFN-gamma positive cells significantly decreased in virgin CD4 subset both in old and nonagenarian subjects, as well as in activated/memory T cells from old in comparison with young subjects. The percentage of TNF-alpha positive cells significantly decreased in activated/memory CD4 subset from old people. Regarding Type 2 cytokines, IL-4 positive cells significantly increased in activated/memory CD4 subset from nonagenarians. On the whole our data indicate that: (1) different Type 1 and Type 2 cytokine-positive CD4 T subsets are differently affected by ageing process; (2) activated/memory T cells appear to be the most affected subset; (3) a shift towards an increased role of Type 2 cytokines and a diminished role of Type 1 cytokines emerges with ageing.
MeSH Terms
- Adult
- Aged
- Aged, 80 and over
- Aging
- Biomarkers
- CD28 Antigens
- CD4-Positive T-Lymphocytes
- Cytokines
- Flow Cytometry
- Humans
- Immunologic Memory
- Inflammation
- Interferon-gamma
- Interleukin-4
- Middle Aged
- T-Lymphocyte Subsets
- Tumor Necrosis Factor-alpha
- fas Receptor
Common variable immunodeficiency (CVID) is primary hypogammaglobulinaemia with an unknown aetiopathogenesis. Although various abnormalities of T and B cells have been described, their pathogenetic roles are unclear. We determined T and B lymphocyte subsets known to be abnormal in CVID in order to disclose possible relations between numerical abnormalities in those cells. Markers associated with B cell development (CD21, CD27, IgM, IgD) were determined on B lymphocytes (CD19 ); T lymphocyte development (CD45RA, CD45RO, CD62L) and activation markers (CD25, CD27, CD28, CD29, CD38, CD57, HLA-DR) were determined on CD4 and CD8 T lymphocytes in 42 CVID patients and in 33 healthy controls. Abnormalities in CD4 T lymphocyte activation markers (increase in CD29, HLA-DR, CD45RO, decrease in CD27, CD62L, CD45RA) were observed particularly in patients with a decreased number of memory (CD27 ) and mature (CD21 ) B cells (group Ia according to the Freiburg group's classification), while abnormalities observed in CD8 cells (increase in CD27 and CD28 and decrease in HLA-DR, CD57 and CD38) did not depend upon grouping patients together according to B lymphocyte developmental subpopulations. We observed correlations between immature B cells (IgM CD21-) and expression of CD27, CD62L, CD45RA, CD45RO and HLA-DR on CD4 T cells in CVID patients but not in the control group. The expression of CD27 and CD45RA on CD4 T lymphocytes, such as the percentage of IgD CD27- and IgD CD27 cells in B lymphocytes, showed age dependency to be more significant than in the control group. Our study demonstrates that T and B lymphocyte abnormalities in CVID are partially related to each other. Some of those abnormalities are not definite, but may evolve with age of the patient.
MeSH Terms
- Adult
- Aging
- Antigens, CD
- Antigens, Differentiation, B-Lymphocyte
- Antigens, Differentiation, T-Lymphocyte
- B-Lymphocyte Subsets
- B-Lymphocytes
- Biomarkers
- CD4-Positive T-Lymphocytes
- CD8-Positive T-Lymphocytes
- Common Variable Immunodeficiency
- Female
- Flow Cytometry
- Humans
- Immunoglobulin D
- Immunoglobulin M
- Lymphocyte Activation
- Male
- Middle Aged
- T-Lymphocytes
In murine studies of immune senescence cell preparations from whole organs, e.g. splenocytes, are frequently reported. However, age-related changes in spleen cell types have been poorly defined throughout the spectrum of adult age or across murine strains. The aim of this study was to use flow cytometry to more fully characterize cell types within the spleen of DBA/2 mice, a strain available from the National Institute of Aging (NIA), across the entire adult age spectrum. In advanced age, B cells comprise a greater percentage of the total splenocyte population, and there is a decline in the percentage of gammadelta T cells in the spleen. The percentage of memory CD4 T cells increases in middle age with a corresponding decrease in the percentage of naïve CD4 T cells. Expression of the co-stimulatory molecule CD28 on splenic CD4 and CD8 T cells increases with age, but CD28 expression on peripheral blood T cells does not change. The senescence marker p16INK4a increases in B cells and CD8 T cells within the spleen and can be measured by flow cytometry.
MeSH Terms
- Aging
- Animals
- Antigens, Surface
- B-Lymphocytes
- Biomarkers
- CD28 Antigens
- CD4-Positive T-Lymphocytes
- CD8-Positive T-Lymphocytes
- Cyclin-Dependent Kinase Inhibitor p16
- Female
- Flow Cytometry
- Immunologic Memory
- Lymphocyte Count
- Mice
- Mice, Inbred DBA
- Spleen
- T-Lymphocytes
Memory T cells can be classified as central memory (T(CM), CD45RA(neg)CCR7( )), effector memory (T(EM), CD45RA(neg)CCR7(neg)), and terminally differentiated cells (T(TD), CD45RA( )CCR7(neg)) with different homing and effector capacities. In 101 healthy subjects aged from 5 to 96 years, distinct dynamics were evidenced between circulating CD4( ) and CD8( ) T cell populations. Naive CD4( ) and CD8( ) T cells decreased linearly with age, CD8( ) twice more rapidly. Memory cells outnumbered naive cells on average at 37.4 in the CD4( ) and 29.5 years of age in the CD8( ) pool. CD4( ) T(CM) and T(EM) cells were positively correlated and increased linearly at a similar rate with age, while CD4( ) T(TD) remained rare. CD8( ) T(EM) and T(TD) accumulated linearly with age, while T(CM) increased only slightly, and each memory subset was negatively correlated to the two others. Almost all CD8( ) T(TD) and some CD8( ) T(EM) had lost CD28 expression. Despite different dynamics, each individual CD4( ) naive and memory subset was correlated to the synonymous CD8( ) subset. Half of the subjects aged 65 years or older were characterized by extremely reduced CD8( ) naive and increased CD8( ) T(TD) cell counts, which could indicate an acceleration of the decay of the immune system from this age onward.
MeSH Terms
- Adolescent
- Adult
- Aged
- Aging
- CD4-Positive T-Lymphocytes
- CD8-Positive T-Lymphocytes
- Cell Differentiation
- Child
- Child, Preschool
- Female
- Humans
- Immunologic Memory
- Infant
- Male
- Middle Aged
The nonagenarian population by definition represents individuals who have demonstrated success in aging. We determined the status of CD8( ) T-cell senescence in nonagenarians by analyzing the expression of CD28 and Fas (CD95), and analyzing activation and activation-induced cell death (AICD). Peripheral blood mononuclear cells (PBMCs) were isolated from three groups of subjects: adults (20-64-year-old), older adults (65-89-year-old), and nonagenarians (>or=90-year-old). PBMCs were stimulated with phytohemagglutinin (PHA) (10 microg/ml). The cells were labeled with conjugated antibodies specific for CD4, CD8, CD28, CD45RO, and Fas, and were analyzed by FACS((R)). There was a strong negative correlation of the percentage of CD28( )Fas(-) CD8( ) T-cells with the age of each individual prior to stimulation in vitro (R(2)=0.76, p<0.0001). Compared to other biomarkers (CD28(-), CD28(-)CD45RO( ), and Fas( )) that have been associated with CD8( ) T-cell aging, the loss of the CD28( )Fas(-) CD8( ) T-cell population exhibited the strongest correlation with the individual's chronologic age. After stimulation with PHA, there was a decrease in the percentage of CD8( ) T-cells from individual >or=65-year-old that expresses both CD28( ) and Fas( ) at day 3. Surprisingly, the AICD response of CD8( ) T-cells at day 7 in the nonagenarians was higher than that in the other two groups. These results suggest that successful aging does not prevent development of the senescent phenotype of unstimulated CD8( ) T cells, but is associated with preservation of CD8 T cell functions including activation and AICD. Increased AICD may result in enhanced rejuvenation capacity of T cells and limit the impact of aging on T cell function in nonagenarians.
MeSH Terms
- Adult
- Aging
- Apoptosis
- Biomarkers
- CD28 Antigens
- CD8-Positive T-Lymphocytes
- Cells, Cultured
- Female
- Gene Expression Regulation
- Humans
- Lymphocyte Activation
- Male
- Middle Aged
- Phytohemagglutinins
- fas Receptor
Lipid rafts are critical to the assembly of the T-cell receptor (TCR) signaling machinery. It is not known whether lipid raft properties differ in CD4 and CD8 T cells and whether there are age-related differences that may account in part for immune senescence. Data presented here showed that time-dependent interleukin-2 (IL-2) production was different between CD4 and CD8 T cells. The defect in IL-2 production by CD4 T cells was not due to lower levels of expression of the TCR or CD28. There was a direct correlation between the activation of p56(Lck) and LAT and their association/recruitment with the lipid raft fractions of CD4 and CD8 T cells. p56Lck, LAT and Akt/PKB were weakly phosphorylated in lipid rafts of stimulated CD4 T cells of elderly as compared to young donors. Lipid rafts undergo changes in their lipid composition (ganglioside M1, cholesterol) in CD4 and CD8 T cells of elderly individuals. This study emphasizes the differential role of lipid rafts in CD4 and CD8 T-cell activation in aging and suggests that the differential localization of CD28 may explain disparities in response to stimulation in human aging.
MeSH Terms
- Adaptor Proteins, Signal Transducing
- Adult
- Aged
- Aging
- CD28 Antigens
- CD4-Positive T-Lymphocytes
- CD8-Positive T-Lymphocytes
- Cholesterol
- Enzyme Activation
- Gangliosides
- Humans
- In Vitro Techniques
- Interleukin-2
- Lymphocyte Specific Protein Tyrosine Kinase p56(lck)
- Membrane Microdomains
- Membrane Proteins
- Middle Aged
- Oncogene Protein v-akt
- Phosphorylation
- Receptors, Antigen, T-Cell
Based on the combined expression of CD27 and CD28, a putative model of T cell differentiation has been previously proposed. We used CD27 and CD28 expression in order to comparatively study the size, cytokine production capacity and proliferative response of CD4 T cell sub-populations from healthy young and elderly volunteers. Elderly persons had a lower percentage of CD27 CD28 but a higher percentage of CD27-CD28 and CD27-CD28-CD4 T cells than the young persons. CD27-CD28-CD4 T cells were present, although at relatively low numbers, in the vast majority of the healthy elderly donors but were only sporadically detected in young persons. Each CD4 T cell sub-population exhibited a distinct phenotype and cytokine production profile, which were not affected by age. When purified CD27 CD28 were stimulated by staphylococcal enterotoxin B, they proliferated to a greater extent than CD27-CD28 and CD27-CD28-CD4 T cells. However, we did not observe age-related differences in proliferative response of each sub-population. We concluded that although the size of the different sub-populations differed between the young and the old group, the functional characteristics of each sub-population were the same in both age groups. This suggests that on a per cell basis there is no functional impairment of CD4 memory T cells in elderly persons. Consequently, potential differences in the function of the total CD4 T cell population are most likely due to different composition of repertoire.
MeSH Terms
- Adult
- Age Factors
- Aged
- Aged, 80 and over
- Aging
- Antigens, Bacterial
- CD28 Antigens
- CD4-Positive T-Lymphocytes
- Cell Proliferation
- Cells, Cultured
- Enterotoxins
- Humans
- Immunologic Memory
- Immunophenotyping
- Middle Aged
- Resting Phase, Cell Cycle
- Telomere
- Tumor Necrosis Factor Receptor Superfamily, Member 7
Aging is associated with dysregulation of immune cells, particularly T cells. Previous studies indicated that vitamin E improves T cell function, in part by a direct effect on T cells. We studied gene expression profile of T cells to better understand the underlying mechanisms of aging- and vitamin E-induced changes in T cell function. Young and old C57BL mice were fed diets containing 30 (control) or 500 (E) ppm of vitamin E for 4 weeks. T cells were purified from splenocytes by negative selection using magnetic beads (anti-Mac-1 and anti-MHC class II), then cultured with media or stimulated with anti-CD3 and anti-CD28. Gene expression profile was assessed using microarray analysis. Genes showing more than two-fold changes, P < 0.05 by ANOVA, and with at least one present call were selected. Aging had significant effects on genes involved in signal transduction, transcriptional regulation, and apoptosis pathways in T cells, while vitamin E had a significant effect on genes associated with the regulation of cell cycle.
MeSH Terms
- Aging
- Animals
- Gene Expression
- Gene Expression Profiling
- Humans
- Immunity
- T-Lymphocytes
- Vitamin E
In spite of the present belief that latent cytomegalovirus (CMV) infection drives CD8 T-cell differentiation and induces premature immune senescence, no systematic studies have so far been performed to compare phenotypical and functional changes in the CD8 T-cell repertoire in CMV-infected and noninfected persons of different age groups. In the present study, number, cytokine production, and growth potential of naive (CD45RA CD28 ), memory (CD45RA- CD28 ), and effector (CD45RA CD28- or CD45RA- CD28-) CD8 T cells were analyzed in young, middle-aged, and elderly clinically healthy persons with a positive or negative CMV antibody serology. Numbers and functional properties of CMVpp65(495-503)-specific CD8 T cells were also studied. We demonstrate that aging as well as CMV infection lead to a decrease in the size of the naive CD8 T-cell pool but to an increase in the number of CD8 effector T cells, which produce gamma interferon but lack substantial growth potential. The size of the CD8 memory T-cell population, which grows well and produces interleukin-2 (IL-2) and IL-4, also increases with aging, but this increase is missing in CMV carriers. Life-long latent CMV infection seems thus to diminish the size of the naive and the early memory T-cell pool and to drive a Th1 polarization within the immune system. This can lead to a reduced diversity of CD8 responses and to chronic inflammatory processes which may be the basis of severe health problems in elderly persons.
MeSH Terms
- Adult
- Aged
- Aging
- Antibodies, Viral
- CD28 Antigens
- CD8-Positive T-Lymphocytes
- Cell Proliferation
- Cytokines
- Cytomegalovirus Infections
- Female
- Humans
- Leukocyte Common Antigens
- Lymphocyte Activation
- Male
- Middle Aged
- T-Lymphocyte Subsets
- Time Factors
The relationship between specific T cell subset alterations and mortality has not been well characterized in older adults. The specific aim was to determine whether specific T cell subsets are associated with an increased risk of death. We conducted a case-control study of T cell subsets (CD4 and CD8 T cells, and subsets of these cells defined by expression or non-expression of CD28, CD45RA, and CD45RO) nested within two complementary prospective cohorts of women aged 65 and over living in the community, the Women's Health and Aging Studies (WHAS). Cases consisted of 61 women who died during 5 years of follow-up, and controls consisted of 61 women matched by age, frailty, and morbidities who survived during 7 years of follow-up. There were no significant differences between cases and controls in any of the T cell subsets studied. When analyses were stratified by frailty status, these data suggest that CD8 CD28- lymphocyte counts were significantly higher among women who were frail compared with pre-frail and non-frail women.
MeSH Terms
- Aged
- Aging
- Antibodies, Viral
- CD28 Antigens
- CD4-Positive T-Lymphocytes
- CD8-Positive T-Lymphocytes
- Case-Control Studies
- Cytomegalovirus
- Female
- Frail Elderly
- Geriatric Assessment
- Humans
- Immunity, Cellular
- Immunophenotyping
- Leukocyte Common Antigens
- Lymphocyte Count
- Maryland
- Mortality
- Residence Characteristics
- T-Lymphocyte Subsets
Killer Ig-like receptors (KIR) are commonly found on human NK cells, gammadelta T cells, and CD8 T cells. Although KIR( ) CD4 T cells are found in certain patients, their prevalence in healthy donors is controversial. We now provide definitive proof that such cells are present in most individuals, and report on their frequency, surface phenotype, cytokine profile, and Ag specificity. The number of KIR( ) CD4 T cells detected in peripheral blood increased with age. In contrast with regular KIR(-) CD4 T cells, the majority of KIR( ) CD4 T cells lacked surface expression of CD27, CD28, CCR4, and CCR7, but did express CD57 and 2B4. In addition, KIR were detected on approximately one-tenth of CD28(-) and CD57( ) memory CD4 T cells. In line with the absence of the Th2 marker CCR4, the KIR( ) CD4 cells produced mainly IFN-gamma and little IL-4, IL-10, or IL-17 upon TCR triggering. Furthermore, the KIR( ) population contained cells that responded to recall Ags in an HLA class II-restricted fashion. Together, our data indicate that KIR-expressing CD4 T cells are predominantly HLA class II-restricted effector memory Th1 cells, and that a significant, previously unrecognized fraction of effector memory Th1 cells expresses KIR.
MeSH Terms
- Adolescent
- Adult
- Aged
- Aged, 80 and over
- Aging
- Amino Acid Sequence
- Animals
- Base Sequence
- CD4 Lymphocyte Count
- CD4-Positive T-Lymphocytes
- Cell Membrane
- Clone Cells
- Epitopes, T-Lymphocyte
- Fetal Blood
- Gene Expression Profiling
- Gene Rearrangement, beta-Chain T-Cell Antigen Receptor
- HLA-D Antigens
- Humans
- Immunologic Memory
- Immunophenotyping
- Mice
- Mice, Transgenic
- Middle Aged
- Molecular Sequence Data
- Receptors, Immunologic
- Receptors, KIR
- Th1 Cells
It is well known that T-lymphocyte proliferation declines ex vivo with age, and is associated with decreased expression and/or activity of stimulatory intracellular signaling proteins. However, the role of inhibitory intracellular signaling molecules like the ubiquitin ligase Cbl-b in regulating T-lymphocyte function in aging is largely unknown. Therefore, we tested the hypothesis that T-lymphocyte proliferation declines with age, in part, due to increased expression of Cbl-b. We show that young splenic T-lymphocytes reduced Cbl-b expression when stimulated with anti-CD3 and anti-CD28 antibodies, while in aged T-lymphocytes the CD28-dependent Cbl-b down-regulation did not occur. This effect did not appear to be due to reduced CD28 receptor expression on aged T-lymphocytes. The mechanism for lack of Cbl-b down-regulation may involve the proteasome since blocking proteasomal activity in young T-lymphocytes prevented Cbl-b down regulation while there was no effect in aged T-lymphocytes on Cbl-b expression. These data provide evidence for a novel mechanism by which aging reduces T-lymphocyte function.
MeSH Terms
- Adaptor Proteins, Signal Transducing
- Aging
- Animals
- Antibodies
- CD28 Antigens
- CD3 Complex
- Cell Proliferation
- Down-Regulation
- Lymphocyte Activation
- Male
- Proteasome Endopeptidase Complex
- Proto-Oncogene Proteins c-cbl
- Rats
- Rats, Sprague-Dawley
- Receptors, Immunologic
- Spleen
- T-Lymphocytes
- Ubiquitin-Protein Ligases
Costimulatory and adhesion molecules are known to play a major role in the pathogenesis of systemic lupus erythematosus. Since fish oil and calorie restriction have been reported to attenuate the development of disease in lupus prone (NZBxNZW)F1 mice, the objective of this study was to assess the expression of these key inflammatory molecules in these mice fed diets differing in n-6 and n-3 fatty acid content and fed either food restricted or ad libitum. Age-associated increases in the expression of CD28, ICAM-1, and PGP-1 molecules that are involved in the recruitment of inflamed lymphocytes into the kidney were attenuated in mice restricted in food intake. The increase in costimulatory (CD80 and CD86) and adhesion (ICAM-1, PGP-1, LFA-1, and Mac-1) in peripheral blood mononuclear cells was also attenuated by food restriction and to a lesser extent by fish oil alone. Interestingly, amelioration of lupus (laminin expression and proteinuria) correlated with the above beneficial effects and could be seen even in 24-month-old mice. In summary, food restriction and fish oil delay the onset of lupus disease and increase life span in B/W mice by prolonging the maintenance of a youthful immune phenotype.
MeSH Terms
- Age Factors
- Animals
- Cell Adhesion Molecules
- Dietary Fats
- Fatty Acids, Omega-3
- Fatty Acids, Omega-6
- Longevity
- Lupus Erythematosus, Systemic
- Mice
Aging is accompanied by a complex dynamics of CD8 T cell subsets whose origin is unclear. To evaluate the impact of Epstein-Barr virus (EBV) and cytomegalovirus (CMV) chronic infections on CD8 T cells in far advanced age, we studied CD8 T cells frequencies and phenotype in nonagenarians and centenarians by HLA-A*0201- and HLA-B*0702-tetramers incorporating epitopes specific of both viruses along with viral replication. The results demonstrate that EBV and CMV infections induce quantitatively and qualitatively different CD8 T-cell responses in advanced aging. The frequency and absolute number of CD8 T cells specific for one lytic and two latent EBV-epitopes, were relatively low and mostly included within CD8 CD28 cells. By contrast, CMV infection was characterized by highly variable numbers of CD8 T cells specific for two differently restricted CMV-epitopes that, in some subjects, were strikingly expanded. Moreover, the great majority of anti-CMV CD8 T cells did not bear CD28 antigen. Notwithstanding the expansion of CMV-specific CD8 lymphocytes, CMV-DNA detection in blood samples was invariably negative. Altogether, we suggest that CMV, but not EBV, can sustain chronic activation of the HLA-class I restricted effector arm in elderly that might have detrimental effects on age-associated diseases.
MeSH Terms
- Aged
- Aged, 80 and over
- Aging
- CD28 Antigens
- CD8-Positive T-Lymphocytes
- Chronic Disease
- Cytomegalovirus
- Cytomegalovirus Infections
- DNA, Viral
- Epitopes
- Epstein-Barr Virus Infections
- Herpesvirus 4, Human
- Histocompatibility Antigens Class I
- Humans
- Leukocytes
- Lymphocyte Activation
- Lymphocytes
Long-term culture studies using CD8 T cells, the immune cells responsible for control of viral infection, have identified the major features of replicative senescence. Aging is associated with increased proportions of CD8 T cells with similar characteristics, such as absence of expression of the CD28 costimulatory molecule and reduced antiviral effector functions. Proinflammatory cytokines produced by senescent CD8 T cells also may exert pleiotropic suppressive effects on overall immune function and bone homeostasis. Thus, modulation of T cell replicative senescence may provide a comprehensive therapeutic strategy to prevent multiple age-associated pathologies.
MeSH Terms
- Aging
- CD28 Antigens
- CD8-Positive T-Lymphocytes
- Cellular Senescence
- Homeostasis
- Humans
- Immune System
- T-Lymphocytes
Like other somatic cells, human T lymphocytes have a finite replicative capacity in vitro, and, by implication and consistent with the limited data available, in vivo as well. An accumulation of dysfunctional T cells may be detrimental under conditions of chronic antigenic stress (chronic infection, cancer, autoimmunity). Using T cells from young donors to model the process of T cell clonal expansion in vitro under these conditions reveals age-associated increasing levels of oxidative DNA damage and microsatellite instability (MSI), coupled with decreasing DNA repair capacity, telomerase induction and telomere length, decreased levels of expression of the T cell costimulator CD28 and consequently reduced secretion of the T cell growth factor interleukin-2 (IL-2). However, data from similar experiments using T cell clones (TCCs) derived from extremely healthy very elderly donors ("successfully aged") indicate that DNA repair is better maintained, MSI less prevalent, and (already short) telomere lengths are maintained. Nonetheless, oxidative DNA damage is seen to the same extent, and clonal longevity is also similar in these clones. DNA damage levels are reduced by culture in 5% oxygen, but longevity is not improved. This may be because of the requirement for intermittent reactivation via receptor pathways dependent on free radical production in T cells. These recent findings from our international immunosenescence research consortium suggest that strategies other than telomere maintenance, better protection against free radicals, or improved DNA repair will be required for functional longevity extension of human TCCs. To obtain sufficient cells for adoptive immunotherapy of cancer, alternative avenues need exploration; currently, these include enforced expression of certain heat shock proteins and proteasome components, and interference with the expression of negative regulatory receptors expressed by T cells.
MeSH Terms
- Antigens
- CD28 Antigens
- CD4-Positive T-Lymphocytes
- Cysteine Endopeptidases
- DNA
- DNA Damage
- DNA Repair
- Free Radicals
- Humans
- Immunotherapy
- Ligands
- Longevity
- Microsatellite Repeats
- Multienzyme Complexes
- Neoplasms
- Oxidative Stress
- Oxygen
- Proteasome Endopeptidase Complex
- T-Lymphocytes
- Telomerase
- Telomere
- Time Factors
- Tumor Necrosis Factor-alpha
Aging is associated with a decline in immune function, particularly within the T cell compartment. Because CD8( ) T cells are critical mediators of protective immunity against cancer, which arises more frequently with advancing age, it is important to understand how aging affects T cell-based antitumor responses. We used our DUC18 T cell/CMS5 tumor model system to examine the ability of both aged APCs and aged, tumor-specific CD8( ) T cells to mount protective responses to tumors in vivo. An assessment of aged DUC18 T cells in vitro showed a naive phenotype, but impaired proliferation in response to anti-CD3 and anti-CD28 stimulation. We found that DCs from young and old recipient mice are comparable phenotypically, and endogenous APCs in these mice are equally able to prime adoptively transferred young DUC18 T cells. Even when aged DUC18 T cells are transferred into aged CMS5-challenged mice, Ag-specific proliferation and CD25 expression are similar to those found when young DUC18 T cells are transferred into young mice. Although trafficking to tumor sites appears unequal, old and young DUC18 T cells reject primary CMS5 challenges to the same degree and with similar kinetics. Overall, we found no loss of endogenous APC function or intrinsic defects in CD8( ) DUC18 T cells with advanced age. Therefore, when young and old tumor-specific T cell populations are equivalently sized, CD8( ) T cell-mediated antitumor immunity in our system is not impaired by age, a finding that has positive implications for T cell-based immunotherapies.
MeSH Terms
- Aging
- Animals
- Antigen-Presenting Cells
- CD8-Positive T-Lymphocytes
- Mice
- Mice, Transgenic
- Neoplasms
- Spleen
- Time Factors
The risk of infection and cancer increases dramatically beyond middle age, when T-cell function is noticeably altered. Nevertheless, many elderly people remain in apparently good health. To identify immunological adaptations favouring longevity, a pilot study was undertaken to compare peripheral blood T cells from healthy volunteers aged 18-25 years with those >65 years. Instead of preserved immune function in the elderly, there was an emergence of haematopoietic space particularly affecting T- and B-cell numbers, together with early signs of immunoglobulin dysregulation. Age-associated proliferative defects were present irrespective of the stimuli used. A higher constitutive expression of NF-kappaB and I-kappaBalpha in the nuclei of peripheral lymphocytes from the elderly remained unaltered by activation stimuli, despite the presence of exogenous cytokines. Nevertheless, activation resulted in their higher CD95 upregulation and more intracellular bcl-2 (suggesting a survival advantage), but lower CD27, CD28 and CD45Rb expression. The presence of CD45RO( ) CD45Rb(-) populations was unique to the elderly and their lower replicative potential was not due to the presence of CD25( ) regulatory T cells. These data collectively suggest altered gene regulation and the accumulation of terminally differentiated T cells during healthy ageing.
MeSH Terms
- Adolescent
- Adult
- Aged
- Aging
- Cell Differentiation
- Cell Division
- Humans
- I-kappa B Proteins
- Immunophenotyping
- Leukocyte Common Antigens
- Leukocyte Count
- Lymphocyte Activation
- NF-KappaB Inhibitor alpha
- NF-kappa B
- Proto-Oncogene Proteins c-bcl-2
- T-Lymphocyte Subsets
- T-Lymphocytes
- fas Receptor
T-cell clones (TCC) derived from human peripheral blood lymphocytes of a young control, a healthy elderly (SENIEUR) donor, or from CD34( ) hematopoietic progenitor cells were utilised in this study to examine how in vivo and in vitro ageing affects T-cell apoptotic capability. The role of CD25, CD28 and the intracellular proteins, FLICE-inhibitory protein (FLIP), receptor-interacting protein (RIP) and caspase 3 were investigated. We observed an age-related decline in the expression of the IL-2 receptor alpha chain CD25, and absence of the co-stimulatory receptor CD28 on three of the four TCC studied. In young donor- and CD34 cell-derived TCC, but not in SENIEUR donor-derived TCC, we observed an age-related increase in susceptibility of the cells to mFas-L-induced apoptosis, which correlated with the age-related decrease of CD25 expression. Expression levels of full-length RIP and FLIP did not show any correlation to apoptotic susceptibility. However, expression levels of the cleaved form of RIP were greatly reduced in the SENIEUR donor-derived TCC, which together with a trend towards increased caspase 3 activity, could indicate an age-related alteration in utilisation of different apoptotic signalling pathways.
MeSH Terms
- Adult
- Aged
- Aged, 80 and over
- Aging
- Antigens, CD34
- Apoptosis
- CASP8 and FADD-Like Apoptosis Regulating Protein
- CD28 Antigens
- Carrier Proteins
- Caspase 3
- Caspases
- Cells, Cultured
- Cellular Senescence
- Hematopoietic Stem Cells
- Humans
- Intracellular Signaling Peptides and Proteins
- Lymphocyte Activation
- Proteins
- Receptor-Interacting Protein Serine-Threonine Kinases
- Receptors, Interleukin-2
- Signal Transduction
- T-Lymphocytes
Elderly persons have been exposed to a myriad of pathogens over their lifespan. This life-long immunological history leads, in some cases, to the generation of expanded populations of memory CD8 T cells that have reached the end stage of replicative senescence. In cell culture, CD8 T cells that are subjected to repeated rounds of antigen-driven proliferation eventually show irreversible cell cycle arrest, permanent and complete loss of CD28 gene expression, apoptosis resistance, reduced gene transcription of the major stress protein in response to heat shock, and shortened telomeres compared to their CD28-expressing progenitors. Clinical studies have documented that high proportions of CD8 T cells that lack CD28 are correlated with reduced antibody response to influenza vaccination and are also an immune marker of increased risk of mortality in persons greater than 80 years of age. In addition, CD8 T cells lacking CD28 expression have been documented to have suppressive influences on immune function. Thus, senescent CD8 T cells may affect immune function both directly and indirectly by modulating other immune cell types. The potential role of senescent T cells in bone homeostasis is suggested as a potentially fruitful area for future investigation. The patterns of cytokine changes observed during the progression to senescence in cell culture are consistent with this possibility, and T cells producing these same cytokines have, in fact, been identified within the bone marrow in murine models of osteoporosis. Interestingly, CD8 T cells with markers of replicative senescence are correlated with increased osteoporotic fractures in the elderly. Thus, senescent CD8 T cells are associated with a variety of deleterious health-related outcomes, suggesting that these cells may exert pleiotropic negative effects on both immune and non-immune organ systems during ageing.
MeSH Terms
- Aging
- Bone Remodeling
- CD8-Positive T-Lymphocytes
- Cellular Senescence
- Estrogens
- Humans
It is commonly believed that the age-related decrease in the ratio CD28( )/CD28(-) among CD8( ) T cells reflects replicative senescence of the lymphocytes. To verify this claim we measured the proliferation of CD8( )CD28( ) and CD8( )CD28(-) subsets by flow cytometry after PHA treatment of mononuclear lymphocytes from donors of different age, including centenarians. The fraction of CD28( ) cells decreases from ca. 80 to 40% (young to centenarians, respectively) with increasing age of the donors. Stimulation by PHA results in an increase in the ratio of CD28( ) relative to CD28(-) in all age groups. We found that not only CD8( )CD28( ) but also CD8( )CD28(-) cells were capable of proliferation. Moreover, the fraction of proliferation-competent CD28(-) cells was higher in the older donors compared with the younger ones. While PHA treatment led to apoptosis (as measured by DNA content and caspase-3 activation) of more than 20% of all lymphocytes, in the CD8( ) subset only ca. 10% died, irrespective of their CD28 status. Altogether, we showed over-representation of proliferating CD8( )CD28(-) cells in aged people, which might not be particularly prone to undergo apoptosis.
MeSH Terms
- Aged
- Aged, 80 and over
- Aging
- Apoptosis
- CD28 Antigens
- CD8-Positive T-Lymphocytes
- Cell Division
- Cells, Cultured
- Cellular Senescence
- Humans
- Immunophenotyping
- Lymphocyte Activation
- Middle Aged
- Phytohemagglutinins
- T-Lymphocyte Subsets
Precise determination of cell cycle length and G(0)-->G(1) transition time of CD4( ) lymphocytes in relation to age was never done before. We show that the cell cycle of healthy elderly donors' CD4( ) cells is significantly shorter, while time to the first division (G(0)-->G(1)) extended compared to cells of young people. The G(0)-->G(1) time inversely correlates with cycle length and the number of CD28 molecules. Quickening of elderly CD4( ) cell divisions depends on overexpression of cyclin D1, possibly related to lowered proteolytic degradation by calpain. Apoptosis eliminates most of responding cells after only one or two divisions, especially in older donors.
MeSH Terms
- Adult
- Aged
- Aging
- Apoptosis
- CD4-Positive T-Lymphocytes
- Calpain
- Cell Cycle
- Cell Division
- Cells, Cultured
- Cyclin D1
- Female
- Humans
- Male
- Middle Aged
The aim of the study was to describe the interrelationship between senescence, depression, and immunity. We assessed 10 elderly patients with depression and 10 age- and sex-matched controls: before, at one and at six month intervals after the anti-influenza vaccination. Levels of TNFalpha, IL6, ACTH, and cortisol, titres of anti-hemagglutinins and anti-neuraminidases, lymphocytes secreting IFNgamma, IL2, IL4, and IL10, cytotoxicity of NK and CD3 CD8 IFNgamma cells, anti-CMV antibodies, and CD28- CD57 lymphocytes known to be associated with the CMV carrier status were evaluated. Higher levels of anti-CMV, higher percentage of the CD28- CD57 cells, and elevated levels of TNFalpha, IL6, and cortisol concomitant with decreased levels of ACTH and insufficient production of IL10 (which increased the IFNgamma /IL10 ratio) were found in the patients suffering from depression, in comparison to healthy controls. The subjects with depression revealed a low NK cytotoxicity, while a level of CD3 CD8 IFNgamma cells was comparable between the groups. Although the levels of anti-hemagglutinins and anti-neuraminidases were low in the depressed patients, they reached the protective titres. The majority of these differences disappeared when CMV titres were entered into the analyses as a covariate. The results suggest that the elderly depressed patients were characterised by increased exposure to CMV in the past, which could have resulted in a pro-inflammatory profile demonstrated as elevated levels of TNFalpha, IL6 and deficiency of suppressive IL10 cells. These changes negatively affect humoral and innate response in the depressed patients.
MeSH Terms
- Aged
- Aged, 80 and over
- Aging
- Antibodies
- Antibodies, Viral
- Antibody Formation
- CD28 Antigens
- Carrier State
- Cytokines
- Cytomegalovirus
- Depression
- Female
- Follow-Up Studies
- Humans
- Hydrocortisone
- Immunization
- Influenza Vaccines
- Interleukin-1
- Interleukin-10
- Interleukin-6
- Lymphocytes
- Male
- Matched-Pair Analysis
- Middle Aged
- Tumor Necrosis Factor-alpha
CD7 and CD28 are T cell Ig superfamily molecules that share common signaling mechanisms. To determine roles CD7 and CD28 might play in peripheral lymphocyte development and function, we have generated CD7/CD28-double-deficient mice. CD7- and CD28-single-deficient and CD7/CD28-double-deficient mice had normal levels of CD4 and CD8-single-positive T cells in thymus and spleen. However, CD28-deficient mice had decreased CD4 CD25 T cells in spleen compared with wild-type mice, and CD7/CD28-double-deficient mice had decreased numbers of CD4 CD25 T cells in both thymus and spleen compared with both wild-type and CD28-deficient mice. Functional studies demonstrated that CD4 CD25 T cells from CD28-deficient and CD7/CD28-double-deficient mice could mediate suppression of CD3 mAb activation of CD4 CD25- wild-type T cells, but were less potent than wild-type CD4 CD25 T regulatory cells. Thyroiditis developed in aged CD7/CD28-double-deficient mice (>1 year) that was not seen in age-matched control mice or single CD7- or CD28-deficient mice, thus suggesting in vivo loss of T regulatory cells allowed for the development of spontaneous thyroiditis. Taken together, these data demonstrated collaborative roles for both CD7 and CD28 in determination of number and function of CD4 CD25 T regulatory cells in the thymus and peripheral immune sites and in the development of spontaneous thyroiditis.
MeSH Terms
- Aging
- Animals
- Antibodies, Monoclonal
- Antigen-Presenting Cells
- Antigens, CD
- Antigens, CD7
- B7-1 Antigen
- B7-2 Antigen
- CD28 Antigens
- CD3 Complex
- CD4-Positive T-Lymphocytes
- CD8-Positive T-Lymphocytes
- Cell Division
- Concanavalin A
- Cytokines
- Down-Regulation
- Homeostasis
- Immunophenotyping
- Leukocyte Count
- Lipopolysaccharides
- Lymphocyte Count
- Lymphopenia
- Male
- Membrane Glycoproteins
- Mice
- Mice, Inbred C57BL
- Mice, Knockout
- Receptors, Interleukin-2
- Spleen
- T-Lymphocyte Subsets
- Thymus Gland
- Thyroiditis
Immune cells are eminently suitable model systems in which to address the possible role of replicative senescence during in vivo aging. Since there are more than 10(8) unique antigen specificities present within the total T lymphocyte population of each individual, the immune response to any single antigen requires massive clonal expansion of the small proportion of T cells whose receptors recognize that antigen. The Hayflick Limit may, therefore, constitute a barrier to effective immune function, at least for those T cells that encounter their specific antigen more than once over the life course. Application of the fibroblast replicative senescence model to the so-called cytotoxic or CD8 T cell, the class of T cells that controls viral infection and cancer, has revealed certain features in common with other cell types as well as several characteristics that are unique to T cells. One senescence-associated change that is T cell-specific is the complete loss of expression of the activation signaling surface molecule, CD28, an alteration that enabled the documentation of high proportions of senescent T cells in vivo. The T cell model has also provided the unique opportunity to analyze telomere dynamics in a cell type that has the ability to upregulate telomerase yet nevertheless undergoes senescence. The intimate involvement of the immune system in the control of pathogens and cancer as well as in modulation of bone homeostasis suggests that more extensive analysis of the full range of characteristics of senescent T cells may help elucidate a broad spectrum of age-associated physiological changes.
MeSH Terms
- Aging
- Cell Division
- Cells, Cultured
- Cellular Senescence
- Humans
- T-Lymphocyte Subsets
- Telomerase
Memory CD8 T cells from old mice can proliferate in nonirradiated recipients. Transfer of labeled cells from aged donors into young recipients showed that proliferation of aged donor CD8 cells requires host cells that can both respond to interferon-gamma and produce interleukin-15. Reisolation of transferred CD8 cells from host mice showed that LAT (linker for activated T cells) translocation to the immunological synapse, and translocation of NF (nuclear factor)-kappaB to the nucleus were diminished in recovered CD8 T cells from old donors, whether they had divided in vivo or not. Cells able to proliferate in vivo could be isolated based on their unusually high levels of CD28 expression, but were found not to differ from other aged CD8 cells in their low levels of LAT and protein kinase C-theta (PKC-theta) translocation to the immunological synapse. Thus in vivo proliferation of CD28hi CD8 cells from aged mice cannot be attributed to retention of T-cell receptor signaling.
MeSH Terms
- Aging
- Animals
- CD28 Antigens
- CD8 Antigens
- CD8-Positive T-Lymphocytes
- Cell Division
- Cells, Cultured
- Interferon-gamma
- Interleukin-15
- Lymphocyte Activation
- Male
- Mice
- Mice, Inbred BALB C
- Mice, Inbred C57BL
- Microscopy, Confocal
- Models, Animal
- Probability
- Receptors, Interferon
- Sensitivity and Specificity
- Signal Transduction
Ligation of CD28, which is present on the majority of CD4( )T cells, promotes proliferation and immune responses. However, expression of CD28 declines with aging, and apoptosis may contribute to this decline. We have investigated the molecular mechanism underlying the decrease in CD28 expression in Jurkat T cells cultured with FasL. FasL blocks expression of CD28 at the transcriptional level. This correlates with activation of caspase cascades: active caspase-3 can be detected and inhibitors of caspase-3 and caspase-8 increase CD28 promoter activity and CD28 expression. These findings are consistent with the hypothesis that apoptosis plays a key role in the age-related decline of CD28 expression and hence in immunosenescence.
MeSH Terms
- 5' Untranslated Regions
- Aging
- Annexins
- Apoptosis
- Blotting, Northern
- Blotting, Western
- CD28 Antigens
- CD3 Complex
- CD4-Positive T-Lymphocytes
- CD8 Antigens
- Caspase 3
- Caspases
- Cellular Senescence
- Cloning, Molecular
- Coloring Agents
- Dose-Response Relationship, Drug
- Down-Regulation
- Enzyme Activation
- Fas Ligand Protein
- Genes, Reporter
- Humans
- In Vitro Techniques
- Jurkat Cells
- Luciferases
- Membrane Glycoproteins
- Models, Biological
- Plasmids
- Promoter Regions, Genetic
- RNA, Messenger
- Tetrazolium Salts
- Thiazoles
- Transcription, Genetic
The age-related decline of immunological functions is well established but it remains largely unknown which specific changes are related to disease. We analyzed peripheral blood lymphocytes of 42 healthy elderly as well as 24 healthy young subjects from southern Brazil. No differences in phytohemagglutinin-induced proliferation and CD4:CD8 ratio were found between the subjects. However, CD4 expression (considering mean fluorescence intensity) was found upregulated in elderly subjects. No changes in activation molecules CD25, CD28, CD69 and CD95 were observed. A reduced proportion of naive (CD45RA ) T cells was found in the elderly compared to young subjects. No changes in adhesion molecule expression (CD11c and CD31) were observed. However, the frequencies of CD49d-positive cells, as well as expression of CD62L, were increased in the eldery subjects. We further described two subgroups of eldery subjects with an immunological risk profile defined by lower CD4:CD8 ratio and reduced proliferative response to mitogens. These data suggest that healthy aging is associated with intact T-cell proliferation and some compensatory immunophenotypical changes.
MeSH Terms
- Adult
- Aged
- Aging
- Antigens, CD
- Brazil
- Female
- Humans
- Immunophenotyping
- Male
- Middle Aged
- T-Lymphocyte Subsets
- T-Lymphocytes
CD28 is the requisite co-stimulatory molecule in the activation of T cells and in the generation of immune responses. But expression of CD28 declined and oxidants accumulated in the elderly. Although accumulation of reactive oxygen species (ROS) during senescence has been reported extensively, the effect of oxidants on CD28-expression remains totally unknown. In this study, we tried to address the molecular mechanism underlying the decrease in CD28-expression of Jurkat T cells cultured in H2O2. Our results indicate that H2O2 could partially block the expression of CD28. This correlates well with a change of nuclear protein binding activity to the motif of site alpha of the CD28 gene, while the site beta-binding activity remained unaltered. On the other hand, since caspase-3 is activated by H2O2, inhibitors of caspase-3 should increase the expression of CD28. What is more interesting is the fact that the site alpha-binding activity was mostly restored after caspase-3 inhibitors had being added. However, caspase-3 is not activated by caspase-8. Maybe it is activated by caspase-9, which is triggered by cytochrome c. We believe that the procaspase-3 is activated by ROS, and the active caspase-3 can induce the change of the site alpha-binding activity, causing a decrease in CD28 expression.
MeSH Terms
- Aging
- CD28 Antigens
- Caspase 3
- Caspase Inhibitors
- Caspases
- Cytochromes c
- Down-Regulation
- Enzyme Inhibitors
- Humans
- Hydrogen Peroxide
- Jurkat Cells
- Oxidative Stress
- Promoter Regions, Genetic
- Protein Binding
- T-Lymphocytes
The ageing process is characterized by a progressive exhaustion of the naïve T cell reservoir that is accompanied by a compensatory expansion of effector/cytotoxic CD8 CD28- T cells. However, the origin and function of this subpopulation is not completely clarified. In this study, we examined the intracellular cytokine profile in purified CD8 T cells obtained from 29 healthy subjects of different ages. Type 1 (IFN-gamma IL-2 and TNF-alpha) and type 2 (IL-4, IL-6 and IL-10) cytokines were determined in three CD8 T subsets, i.e. CD95-CD28 (naïve), CD95 CD28- (effector/cytotoxic), and CD95 CD28 (memory). As a general trend, we observed, in aged subjects, an increase of type 1 and type 2 intracellular cytokines within the three CD8 subsets. In particular, we showed that type 1 cytokine-positive cells significantly increased, with age, among all the CD8 subsets, while a marked increase of type 2 producing cells was observed only in memory CD8 T cells. These profound changes are compatible with inflame-aging, an hypothesis which suggest that immunosenescence is mainly driven by a chronic antigenic load which not only induces an enormous expansion of CD28- T cells, but also increases their functional activity, exemplified by an high frequency of cells positive for pro-inflammatory cytokines.
MeSH Terms
- Adult
- Aged
- Aged, 80 and over
- Aging
- Analysis of Variance
- CD8-Positive T-Lymphocytes
- Cytokines
- Flow Cytometry
- Humans
- Immunologic Memory
- Immunophenotyping
- Inflammation
- Lymphocyte Activation
- Middle Aged
- T-Lymphocyte Subsets
- T-Lymphocytes, Cytotoxic
The age-related modulation of lymphocyte number and function was assessed in a nonhuman primate model consisting of healthy olive baboons (Papio cynocephalus anubis) of ages encompassing the entire life span of this species. The objectives of this study were to characterize an animal model of immunosenescence and to assess whether or not age should be considered when designing studies for the evaluation of vaccine candidates in baboons. Specifically the following parameters were assessed in baboons from 6 months to 26 years of age: relative numbers of B lymphocytes, CD4 and CD8 T lymphocytes, and T lymphocytes expressing CD28, CD25, and phytohemagglutinin-stimulated lymphoproliferative activity; and concentrations of total immunoglobulin, soluble interleukin-2 receptor alpha, and soluble CD30 in serum. There was a statistically significant effect of age on lymphocyte numbers. As age increased, relative B-cell numbers (ranging from 6 to 50%) decreased (P < 0.001) and relative T-cell numbers (ranging from 28 to 80%) increased (P < 0.001). The increase in T-cell numbers involved both the CD4 and CD8 subsets. In addition, there was a significant negative correlation of age with levels of soluble interleukin-2 receptor alpha in serum. Modulation of lymphocyte numbers appears to occur gradually during the entire baboon life span, thus suggesting the presence of an age-related developmentally regulated process. These findings indicate that baboons represent a potentially useful model to study selected phenomena related to immunosenescence. These findings also indicate that, when using the baboon model for vaccine or other experimental protocols requiring the assessment of immune responses, it would be appropriate to take into account the age of the animals in the study design.
MeSH Terms
- Aging
- Animals
- Antigens, CD
- Enzyme-Linked Immunosorbent Assay
- Female
- Flow Cytometry
- Immunoglobulins
- Immunophenotyping
- Lymphocytes
- Male
- Papio
Longitudinal studies suggest that a set of immune parameters including high percentages of peripheral CD8 , CD28-, CD57 T lymphocytes, low CD4 and B cell counts, and poor T cell proliferative responses to mitogens is associated with decreased remaining longevity in the free-living very elderly (> 85 years). This combination of immune parameters was also significantly associated with an inverted CD4/CD8 ratio and cytomegalovirus seropositivity. Here, using tetramer technology, we show markedly increased numbers of CD8 T cells bearing receptors for one single CMV epitope in the very elderly. Moreover, the fraction of these tetramer-reactive cells secreting interferon-gamma after specific antigenic stimulation was significantly lower in the old than in the young, as was the percentage of CD28-positive cells in this population. Therefore, we conclude that marked expansions of CMV-specific CD8 T cells have occurred and that the obsession of a large fraction of the entire CD8 T cell subset with one single viral epitope may contribute to the increased incidence of infectious disease in the elderly by shrinking the T cell repertoire available for responses to other antigens.
MeSH Terms
- Adult
- Aged
- Aged, 80 and over
- Aging
- Biomarkers
- CD4-CD8 Ratio
- CD8-Positive T-Lymphocytes
- Cytomegalovirus
- Cytomegalovirus Infections
- Epitopes
- Female
- Flow Cytometry
- Humans
- Immunoglobulin G
- Interferon-gamma
- Longitudinal Studies
- Lymphocyte Count
- Male
- Middle Aged
- Receptors, Antigen, T-Cell
- T-Lymphocyte Subsets
Current disease models of autoimmune syndromes, such as rheumatoid arthritis, propose that chronic inflammation is caused by 'forbidden T-cell clones' that recognize disease-inducing antigens and drive tissue-injurious immune reactions. Reappraisal of disease incidence data, however, emphasizes that rheumatoid arthritis is a syndrome of the elderly that occurs with highest likelihood in individuals in whom the processes of T-cell generation and T-cell repertoire formation are compromised. Thymic T-cell production declines rapidly with advancing age. Multiple mechanisms, including antigen-driven clonal expansion and homeostasis-driven autoproliferation of post-thymic T cells, impose replicative stress on T cells and induce the biological program of cellular senescence. T-cell immunosenescence is associated with profound changes in T-cell functional profile and leads to accumulation of CD4 T cells that have lost CD28 but have gained killer immunoglobulin-like receptors and cytolytic capability and produce large amounts of interferon-gamma. In patients with rheumatoid arthritis, T-cell immunosenescence occurs prematurely, probably due to a deficiency in the ability to generate sufficient numbers of novel T cells. We propose that autoimmunity in rheumatoid arthritis is a consequence of immunodegeneration that is associated with age-inappropriate remodeling of the T-cell pool.
MeSH Terms
- Adult
- Aged
- Aging
- Antigens, CD
- Arthritis, Rheumatoid
- Autoimmunity
- CD4-Positive T-Lymphocytes
- Cellular Senescence
- Coronary Artery Disease
- Humans
- Immune System
- Lymphocyte Count
- Middle Aged
- Thymus Gland
In a genome-wide ENU mouse mutagenesis screen a recessive mouse mutation, unmodulated, was isolated with profound defects in humoral immune responses, selective deficits in B cell activation by antigen receptors and T cell costimulation by CD28, and gradual development of atopic dermatitis with hyper-IgE. Mutant B cells are specifically defective in forming connections between antigen receptors and two key signaling pathways for immunogenic responses, NF-kappaB and JNK, but signal normally to calcium, NFAT, and ERK. The mutation alters a conserved leucine in the coiled-coil domain of CARMA-1/CARD11, a member of the MAGUK protein family implicated in organizing multimolecular signaling complexes. These results define Carma-1 as a key regulator of the plasticity in antigen receptor signaling that underpins opposing mechanisms of immunity and tolerance.
MeSH Terms
- Aging
- Amino Acid Sequence
- Animals
- Antibody Formation
- B-Lymphocytes
- Dermatitis
- Guanylate Kinases
- JNK Mitogen-Activated Protein Kinases
- Mice
- Mitogen-Activated Protein Kinases
- Molecular Sequence Data
- Mutagenesis
- NF-kappa B
- Nucleoside-Phosphate Kinase
- T-Lymphocytes
Older age is a strong predictor of accelerated human immunodeficiency virus (HIV) disease progression. We investigated the possible immunologic basis of this interaction by comparing older (>/=45 years) and younger (</=30 years) HIV-infected adults with simultaneously enrolled, aged-matched, healthy volunteers. Cross-sectional comparisons suggested age-associated reductions in naive CD8( ) cells and in the expression of CD28( ) on CD8( ) cells among both HIV-infected subjects and control subjects. Opposite patterns of CD4( ) and CD8( ) cell differences were apparent between these subject groups. HIV infection, but not age, was associated with impairments in delayed-type hypersensitivity responses, lymphoproliferation, and spontaneous apoptosis and with alterations in expression of chemokine receptors CCR5 and CXCR4. Reduced thymic volumes were associated with age and with HIV infection among younger, but not older, subjects. Because of their common association with age and HIV disease, naive CD8( ) cell depletion, diminished CD28 expression on CD8( ) cells, and reduced thymic volumes are possible correlates of the interaction of age with HIV disease.
MeSH Terms
- Adolescent
- Adult
- Aged
- Aging
- CD28 Antigens
- CD8-Positive T-Lymphocytes
- Cross-Sectional Studies
- Disease Progression
- Female
- Gene Expression Regulation
- HIV Infections
- HIV-1
- Humans
- Male
- Middle Aged
- Phenotype
- Thymus Gland
The age-related increase of peripheral CD4 CD8 double-positive (DP) T cells in cynomolgus monkeys has been reported previously. Because the percentage of DP T cells in cynomolgus monkeys increases abruptly in parallel with the thymic involution occurring at around 11 years of age, it was suggested that thymic involution was associated with this increase. Therefore, a longitudinal study was carried out over 5 years to clarify the exact time when DP T lymphocytes start to increase in relation to the thymic involution. Twelve cynomolgus monkeys at 6 years of age were classified into three groups, based on their percentage of DP T cells, as follows: DP-High (>5% DP T cells); DP-Middle (1-5% DP T cells); and DP-Low (<1% DP T cells). In the DP-High group, the percentage of DP T cells showed an abrupt increase, of >10%, in monkeys at 7 years of age, and the prevalence of this subset correlated with a distinctive increase in the percentage of memory T cells (CD4 CD29(high), CD8 CD28-), indicating an association with the maturation of immune function, including thymic involution. To assess the thymic function, the coding joint of T-cell receptor excision circles (cjTREC) levels in sorted T cells were analysed by polymerase chain reaction (PCR)-enzyme-linked immunosorbent assay (ELISA). The cjTREC in the T cells of the DP-High group (4362 /- 3139 copies/105 T cells) was significantly lower than that (22 722 /- 4928 copies/105 T cells) of the DP-Low group. Moreover, the mean copy number of cjTREC in naive T cells was also significantly different between the DP-High and the DP-Low group (0.457 /- 0.181 and 1.141 /- 0.107, respectively). These findings suggest that thymic involution has an influence on the age-related increase of DP T cells in cynomolgus monkeys.
MeSH Terms
- Aging
- Animals
- CD4-Positive T-Lymphocytes
- CD8-Positive T-Lymphocytes
- Immunophenotyping
- Longitudinal Studies
- Lymphocyte Count
- Macaca fascicularis
- T-Lymphocyte Subsets
- Thymus Gland
So far, very few studies exist on the naïve T cell population of elderly persons. Only recently an increase in the percentage of long lived CD4( )CD31(-) naïve T cells has been claimed to occur with aging. We, therefore, characterised CD31( ) and CD31(-) CD45RA( ) CD4( ) T cells in young and healthy elderly persons. The production of IL-2 and IFN-gamma by the different subpopulations was studied following stimulation with PMA and Ionomycin. The expression of CD28, CD11a, CD62L, CXCR3 and CCR7 was also analysed. The results of this study demonstrate a pronounced increase in the percentage of CD31(-) CD45RA( ) T cells within the CD4 subpopulation of elderly persons. Both, CD31(-) and CD31( ) CD45RA( ) cells expressed CD28, CD62L, were CD11a (dim) and produced IL-2 but no IFN-gamma. This phenotype confirms that they were naïve T cells. IL-2 production by naïve T cells was not impaired in elderly persons. Interestingly, CD31( ) as well as CD31(-) naïve T cells contained a subpopulation of CXCR3( ) cells in elderly individuals, but not in young ones. In spite of expressing this chemokine receptor that enables the cells to migrate into inflammatory tissues, they were still CCR7( ) and CD62L( ). We speculate that due to previous contact with local environmental factors, this subset of naïve T cells acquires a different chemokine receptor phenotype, resulting in an altered migratory capacity in old age. Aberrant contact with antigen and effector cell differentiation in unorthodox locations may be the consequence. This could also affect Th1/Th2 polarisation, which is known to be impaired in elderly persons.
MeSH Terms
- Adult
- Aged
- Aging
- Biomarkers
- CD4 Antigens
- CD4-Positive T-Lymphocytes
- Cell Adhesion
- Cell Movement
- Cohort Studies
- Female
- Humans
- Immunophenotyping
- Leukocyte Common Antigens
- Male
- Middle Aged
- Platelet Endothelial Cell Adhesion Molecule-1
- Receptors, CXCR3
- Receptors, Chemokine
- Th1 Cells
- Th2 Cells
As during replicative senescence either in vivo or in vitro, the growing up subpopulation of CD8 CD28- cells is observed, we compared replicative senescence of T cells derived from mononuclear cells of peripheral blood (PBMC) of adults with those from cord blood (CBMC), not having yet CD8 CD28- subpopulation. In PHA-stimulated and IL-2-dependent cultures, T cells from both cord blood and peripheral blood of young adults displayed similar pattern of replicative senescence characterised by gradual decrease of proliferation capacity (assessed by CFSE assay) and reduction of CD28 subpopulation of CD8 cells. We were also interested whether CD8 CD28- were just progeny of CD28 cells or if they were able to proliferate by themselves. After PHA stimulation of cells from adult donors at different ages, including centenarians, the transient up-regulation of CD28 was observed. In CBMC and PBMC from young donors, the entire CD28 subpopulation entered the cell cycle. In PBMC, from the majority of middle-aged subjects and all centenarians both CD28 and CD28- were proliferating. All together we can conclude that in vitro CD8 CD28- are the progeny of both CD8 CD28 and CD8 CD28- subpopulations.
MeSH Terms
- Adult
- Aged
- Aged, 80 and over
- Aging
- CD28 Antigens
- CD8 Antigens
- CD8-Positive T-Lymphocytes
- Cell Division
- Cells, Cultured
- Female
- Fetal Blood
- Humans
- Immunophenotyping
- Infant, Newborn
- Male
- Middle Aged
- Phytohemagglutinins
The purpose of this study was to investigate the immunosenescence of skin-homing T cells expressing the cutaneous lymphocyte antigen (CLA). Peripheral blood lymphocytes from 72 healthy individuals (33 male and 39 female; median age 54 years; age-range: 18-94 years) were investigated. The expression of CD28, CD45RA and CD45RO, as well as intracellular interferon-gamma (IFN-gamma) and interleukin-4 (IL-4) formation of CLA 'skin homing' T cells, was analysed. In addition, T cells were detected immunohistologically in skin specimens from 15 young and 15 old, healthy individuals. The relative telomere length (RTL) was measured by fluorescence in situ hybridization using flow cytometry (flow FISH). The total number of CLA T cells was found to remain constant with increasing age. In contrast to peripheral blood T cells (CD3 CLA-), which showed significantly decreased CD28 and CD45RA expression in donors > 60 years of age, no age-related alterations of either CD28 CLA T cells or CD45RA CLA T cells were observed. In the group of donors > 60 years of age, the proportion of intracellular IFN-gamma-producing CD3 CLA- cells showed a significant increase, whereas the number of IFN-gamma- and IL-4-producing CLA T cells was not affected by age. After stimulation with phytohaemagglutinin (PHA) or staphylococcal enterotoxin B (SEB), CLA T cells from old donors did not show a reduced response compared with CLA T cells from young donors. Additionally, the counts of T cells in healthy skin from young and old adults were statistically not different. Furthermore, the RTL was significantly shortened in enriched CD45RO CLA- T cells from healthy old individuals, but not in aged CLA T cells. The present data suggest that CLA T cells might be a T-cell subpopulation which does not undergo immunosenescence. This may explain why the intensity of inflammatory skin reactions (e.g. psoriasis or eczema) seems to be independent of the patients' age.
MeSH Terms
- Adolescent
- Adult
- Aged
- Aged, 80 and over
- Aging
- Antigens, Differentiation, T-Lymphocyte
- Antigens, Neoplasm
- CD28 Antigens
- Cells, Cultured
- Female
- Humans
- In Situ Hybridization, Fluorescence
- Interferon-gamma
- Interleukin-4
- Leukocyte Common Antigens
- Lymphocyte Activation
- Male
- Membrane Glycoproteins
- Middle Aged
- Skin
- T-Lymphocyte Subsets
- Telomere
The elderly suffer from an increased incidence of infectious disease, accompanied by increased morbidity and mortality. Interferon-gamma plays an important role in defense against intracellular pathogens such as mycobacteria and viruses. A reduced capacity to produce this cytokine in the elderly, as demonstrated by our findings of significant decreases in IFN-gamma production in vitro on stimulation with bacterial products (LPS) or viral antigens (influenza vaccine), might therefore contribute to disease susceptibility. Moreover, accumulating data suggest that persistent infection with EBV and particularly CMV impacts upon the immune system in aging and may contribute to the immune risk phenotype (IRP), which predicts remaining longevity in the very elderly. Using tetramer technology and IFN-gamma ELISPOT assays, we found that the commonly-observed clonal expansions of CD8 T-cells in the elderly were for the most part poorly-functional CMV- and EBV-specific cells, expressing little CD28. The resulting accumulation of dysfunctional cells may lead to a reduction of the repertoire of functional T-cells available for responses to novel antigens. Further longitudinal studies are needed to demonstrate whether cytokines such as IFN-g are also part of the IRP. Improving the definition of the IRP will help to understand and thus prevent or reverse age-associated immune dysfunction.
MeSH Terms
- Aged
- Aging
- Animals
- Antigens, Viral
- CD8-Positive T-Lymphocytes
- Humans
- Infections
- Interferon-gamma
- Phenotype
- Risk Factors
An increased production of proinflammatory cytokines occurs in a high percentage of elderly persons and is associated with an impaired humoral immune response. However, high IL-4 production has also been observed in old age. We now demonstrate an IL-4-producing subpopulation of CD8 T cells in a subgroup of healthy older adults. This T cell subset is substantial in size and has a characteristic phenotype expressing CD45RO, CD28, CD62L, and CD25. IL-4-producing CD8 T cells produce large amounts of IL-2 but not IFN-gamma or perforin, and these cells do not have a regulatory suppressive effect on other T cells. In vivo IL-4-producing CD8 T cells can be stably detected over a year. When put into culture they also have a stable cytokine production pattern but fail to produce perforin even in the presence of IL-12. This special T cell type does not occur in persons under the age of 40, but is present in 36% of the persons >60 years of age. In this age group, IL-4-producing CD8 T cells are more frequent in persons who are still capable of raising a humoral immune response following immunization than in others who fail to produce protective Abs after vaccination. Our results suggest that CD8 T cells with a CD62L (bright) phenotype accumulate in a subgroup of older adults. Due to their phenotype that enables them to migrate into lymphoid tissues and to their capacity to produce IL-4, these cells may counterbalance the overproduction of proinflammatory cytokines in old age.
MeSH Terms
- Adult
- Aged
- Aged, 80 and over
- Aging
- Antibodies, Viral
- CD8-Positive T-Lymphocytes
- Cells, Cultured
- Female
- Humans
- Immunophenotyping
- Influenza Vaccines
- Interferon-gamma
- Interleukin-4
- L-Selectin
- Leukocyte Common Antigens
- Lymphocyte Activation
- Lymphocyte Count
- Lymphocyte Culture Test, Mixed
- Male
- Membrane Glycoproteins
- Middle Aged
- Perforin
- Pore Forming Cytotoxic Proteins
- Receptors, Antigen, T-Cell
- T-Lymphocyte Subsets
- T-Lymphocytes, Regulatory
The aging associates to it unites alteration of the immune response, this is well documented. This alteration can contribute to much of the illnesses associated to the age like repetition infections, cancer and illnesses autoinmunes. Is in the immunity mediated by cells where the main dysfunction resides, although with accuracy it is not clarified which is the intimate cause that produces it, although certainly the smallest presence in a co-estimulative of the recognition and the immune response as the receiver CD28, seem to play a key paper between to the descent of the thymic activity. The relationship between immunity and nutrition is known, as well as the high nutritional deficit prevalence in the elderly. In this work we pass reviews to that published in relation to the possibilities of improving the immune response in the elderly with nutritional treatments.
MeSH Terms
- Aged
- Aging
- Dietary Supplements
- Humans
- Immune System
- Micronutrients
- Nutritional Physiological Phenomena
The age-related impairment of phytohaemagglutinin (PHA)-triggered peripheral blood mononuclear cell (PBMC) proliferation was paralleled by an expansion of CD28 (-) T lymphocytes with a poor capacity to undergo lectin-induced blastogenesis. However, both CD28 (-) and CD28 ( ) T cells isolated from aged individuals exhibited a significant reduction of proliferative response to PHA in comparison with young controls, this implies that the CD28-mediated signaling is not the only defective pathway in the elderly. Thus, PBMC or T cell subsets plus monocytes from aged donors were stimulated with PHA and assayed for the production of, or the response to cytokines known to regulate T cell functions. Results can be so summarized: (i). interleukin (IL)-2 as well as IL-10 release was unaffected by age; (ii). in both groups of subjects, IL-15 concentrations were similar to those spontaneously released by PBMC; (iii). surprisingly, IL-12 p70 and IL-12 p40 production by PBMC was markedly increased in the aged group; (iv) in spite of this finding and of the experimental outcome that IFN-gamma synthesis was almost completely dependent on IL-12. PBMC from old individuals did not release higher amounts of IFN-gamma in comparison with young controls; (v). moreover, only a slight increase in IFN-gamma production was observed in PBMC cultures from the aged group as a result of IL-12 and/or IL-15 costimulation; (vi) at the same time, even though IL-12 as well as IL-15 were necessary for an efficient T cell proliferation, the addition of exceeding doses of cytokines proved to be ineffective in enhancing the proliferative outcome of PBMC or of both CD28 ( ) and CD28 (-) T cells in the aged group. Taken together, the data outline the role of CD28 and IL-12/IL-15 signaling impairment in T cell proliferative deficiency during senescence.
MeSH Terms
- Adult
- Aged
- Aged, 80 and over
- Aging
- Antigen-Presenting Cells
- CD28 Antigens
- Cell Division
- Cells, Cultured
- Female
- Humans
- Interferon-gamma
- Interleukin-10
- Interleukin-12
- Interleukin-15
- Interleukin-2
- Leukocytes, Mononuclear
- Male
- Phytohemagglutinins
- Signal Transduction
- T-Lymphocyte Subsets
- T-Lymphocytes
The immune system gradually becomes anergic with age. Here, we measured intracellular levels of cytotoxic T-lymphocyte-associated antigen 4 (CTLA-4), a negative regulator of T-cells, in 53 healthy individuals aged 18-94. We found a highly significant correlation between age and percent of CTLA-4 CD4 cells (r=0.6, P<0.001) and between age and mean fluorescence intensities of CTLA-4 (i.e. number of molecules, r=0.61, P<0.001). CTLA-4 levels were also correlated with immune activation, determined by levels of HLA-DR CD3 cells (r=0.55, P<0.001). We postulate that immune senescence associated with age is caused in part by chronic immune activation with related decrease in CD28 costimulatory molecules and increase in inhibitory CTLA-4 molecules.
MeSH Terms
- Abatacept
- Aging
- Antigens, CD
- Antigens, Differentiation
- CD28 Antigens
- CTLA-4 Antigen
- Humans
- Immunoconjugates
- T-Lymphocytes
- Up-Regulation
Using carboxyfluorescein diacetate succinimidyl ester (CFSE)-tagged cells to measure proliferation in vivo, we found that only memory CD8( ) cells from mice older than 18 months gave measurable levels of proliferation and that the proportion of memory CD8( ) T cells able to proliferate in a nonirradiated recipient increased with age. CD8 cells that had proliferated in vivo contained higher levels of CD28 when compared to CD8 cells that had not divided. Cells with high levels of CD28 were preferentially able to divide in nonirradiated recipients. Using ex vivo intracellular staining analysis, we determined that most of the CD8( ) T cells that were capable of dividing in vivo produced IFN-gamma after isolation from recipient mice or their original host. These studies thus document the presence in aged mice of a population of CD28(hi) CD8( ) cells whose ability to proliferate in vivo without antigenic stimulation and to produce IFN-gamma may be involved in immune regulation.
MeSH Terms
- Aging
- Animals
- CD28 Antigens
- CD8-Positive T-Lymphocytes
- Immunologic Memory
- Immunophenotyping
- Interferon-gamma
- Interleukin-4
- Lymphocyte Activation
- Male
- Mice
- Mice, Inbred BALB C
- Mice, Inbred C57BL
- Proto-Oncogene Proteins c-bcl-2
The plethora of changes associated with immunosenescence radically alters virtually all aspects of immune responsiveness. How this transformation effects resolution of an infectious challenge is addressed in this study. A well-established infection model was used; Trichuris muris, a cecum-dwelling helminth, is natural to mice, and infection in different strains results in clearly polarized responses. A dominating T helper 2 (Th2) response orchestrates immunity, whereas a Th1 response will result in susceptibility. Mice between 19 and 28 months old were more susceptible to infection, whereas 3-month-old mice of the same strain demonstrated the resistant phenotype. The cytokine response made by these aged mice was clearly altered at the site of infection, and within the local draining lymph nodes higher Th1 and lower Th2 cytokine levels were found, both at the protein and RNA level. Confirming these changes, aged mice also showed a delayed parasite-specific immunoglobulin G1 response and intestinal mastocytosis, both of which are driven by Th2 cytokines. To address possible causes of the observed immune deviation, purified CD4 cells from both young and aged mice were stimulated in vitro. Cells from aged mice did not respond to stimulation via CD28 and in vitro were less able to proliferate and polarize into Th2 cells; Th1 polarization was found to be normal. Together these data suggest that changes in cytokine phenotype, particularly CD4 cells, contribute to the observed age-associated switch from T. muris resistance to susceptibility.
MeSH Terms
- Aging
- Animals
- Antibodies, Helminth
- CD28 Antigens
- Cytokines
- Female
- In Vitro Techniques
- Intestine, Large
- Lymphocyte Activation
- Male
- Mice
- Mice, Inbred C57BL
- RNA, Messenger
- Th1 Cells
- Th2 Cells
- Trichuriasis
- Trichuris
Young mice lacking CD28 have normal numbers of peripheral B cells; however, abnormalities exist in the humoral immune response that may result from an intrinsic defect in the B cells. The goal of this study was to assess whether CD28 could be involved in the development of B cells. CD28 mRNA was detected preferentially in the fraction of bone marrow enriched for stromal cells. Flow cytometry and RT-PCR analysis demonstrated that CD28 was also expressed by primary-cultured stromal cells that supported B lymphopoiesis. Confocal microscopy revealed that in the presence of B-lineage cells, CD28 was localized at the contact interface between B cell precursors and stromal cells. In addition, CD80 was detected on 2-6% of freshly isolated pro- and pre-B cells, and IL-7 stimulation led to induction of CD86 on 15-20% of pro- and pre-B cells. We also observed that stromal cell-dependent production of B-lineage cells in vitro was greater on stromal cells that lacked CD28. Finally, the frequencies of B-lineage precursors in the marrow from young (4- to 8-wk-old) CD28(-/-) mice were similar to those in wild-type mice; however, older CD28(-/-) mice (15-19 mo old) exhibited a 30% decrease in pro-B cells and a 50% decrease in pre-B cells vs age-matched controls. Our results suggest that CD28 on bone marrow stromal cells participates in stromal-dependent regulation of B-lineage cells in the bone marrow. The localization of CD28 at the stromal cell:B cell precursor interface suggests that molecules important for T cell:B cell interactions in the periphery may also participate in stromal cell:B cell precursor interactions in the bone marrow.
MeSH Terms
- Aging
- Animals
- B-Lymphocyte Subsets
- Bone Marrow Cells
- CD28 Antigens
- Cell Communication
- Cell Differentiation
- Cell Division
- Cell Line
- Cell Lineage
- Cell Survival
- Cells, Cultured
- Female
- Ligands
- Mice
- Mice, Inbred BALB C
- Mice, Inbred C57BL
- Mice, Knockout
- Stem Cells
- Stromal Cells
- T-Lymphocyte Subsets
A favorable incidence and severity of graft-vs-host disease is observed in patients transplanted with banked, unrelated, HLA-mismatched umbilical cord blood (UCB) grafts, while the incidence of malignant relapse remains low. CTLA-4 mediates negative T-cell signaling and may contribute to the development of allogeneic tolerance. In this study, we compared protein and mRNA expression of CTLA-4 in stimulated UCB and adult peripheral blood T cells. T cells were isolated from UCB and adult peripheral blood and stimulated with anti-CD3 and anti-CD28 monoclonal antibodies. Cells were immunostained and analyzed by flow cytometry for both surface and intracellular expression of CTLA-4 in the presence and absence of cyclosporin A, and kinetics of CTLA-4 expression compared. CTLA-4 mRNA expression was measured using quantitative real-time polymerase chain reaction. NFAT1 protein levels were measured by Western blot analysis. These studies demonstrate reduced surface and intracellular expression of CTLA-4 in stimulated UCB T cells compared to adult controls. Furthermore, reduced CTLA-4 protein expression in UCB T cells was noted to be in part transcriptionally regulated, as CTLA-4 mRNA levels also were significantly lower. Reduced CLTA-4 expression by UCB T cells followed the kinetics of delayed and reduced expression of the transcription factor NFAT1 by UCB T lymphocytes during primary stimulation. Moreover, cyclosporin A, which is known to modulate NFAT activation, reduced CTLA-4 protein expression in adult and UCB T cells. Reduced expression of the key regulatory proteins CTLA-4 and NFAT-1 may contribute to favorable UCB T lymphocyte allogeneic responses.
MeSH Terms
- Abatacept
- Adult
- Aging
- Antigens, CD
- Antigens, Differentiation
- CTLA-4 Antigen
- Cell Division
- Cyclosporine
- DNA-Binding Proteins
- Fetal Blood
- Flow Cytometry
- Gene Expression Regulation
- Graft vs Host Disease
- Hematopoietic Stem Cell Transplantation
- Humans
- Immune Tolerance
- Immunoconjugates
- Immunosuppressive Agents
- Infant, Newborn
- Lymphocyte Activation
- NFATC Transcription Factors
- Nuclear Proteins
- Polymerase Chain Reaction
- RNA, Messenger
- T-Lymphocytes
- Transcription Factors
- Transcription, Genetic
The mechanism of the age-associated decrease in CD8 T cell response of mice to virus infection was examined in young adult (6 months) and aged (22 months) C57BL/6 mice during primary pulmonary influenza A virus infection. A significant age-associated decrease in both the percentage (P<0.0001) and number (P<0.05) of CD8 T cells binding MHC Class I tetramers containing influenza A nucleoprotein (NP) epitope and in virus-specific CTL activity (P<0.05) was observed with pulmonary lymphocytes. The percentage of NP CD8 cells of individual mice strongly correlated with NP-specific cytotoxic activity (r(2)=0.77, P<0.02) and with the percentage of CD8 cells that produced interferon-gamma (r(2)=0.86, P<0.002) in both young and aged mice. Comparable expression of the CD28, CD25, and the memory CD44(hi)/CD62L(lo) phenotype was detected on NP CD8 lymphocytes from mice of both age groups. There was a delay in the maximal expansion of NP CD8 cells in aged compared to young mice that paralleled a delay in maximal cytotoxic activity and in virus clearance. These data suggest that the age-related impairment of CD8 lymphocyte activity during a primary influenza A infection is due to a defect in the expansion, rather than in effector activity, of influenza-specific CD8 T cells.
MeSH Terms
- Aging
- Animals
- CD8-Positive T-Lymphocytes
- Disease Models, Animal
- Epitopes, T-Lymphocyte
- Humans
- Immunophenotyping
- Influenza A virus
- Influenza, Human
- Interferon-gamma
- Lung
- Mice
- Mice, Inbred C57BL
- Nucleocapsid Proteins
- Nucleoproteins
- RNA-Binding Proteins
- Viral Core Proteins
An expression of the surface co-stimulatory molecules-the CD152 and the CD28 has been compared between young and old individuals on the CD8(high ) lymphocytes. Sixty five elderly healthy (65-96 years old) and 31 young (19-40 years old) volunteers were examined. An expression of CD152 and CD28 surface antigens was analyzed by flow cytometry ex vivo and on whole blood cell cultures lymphocytes stimulated with interleukin 2 (IL2). The elderly population was characterized by a lower percentage of the CD8(high ) lymphocytes than the young population. The percentages of CD28( ) lymphocytes as well as those of CD8(high )CD28( ) subpopulation were lower in the old group compared to the young group. The surface expression of CD152 antigen was similar to that of CD28 with a lower percentage of the CD152( ) lymphocytes and CD8(high )CD152( ) cells in the old group. Stimulation of lymphocytes in vitro with IL2 resulted in an increase of the CD8(high )CD152( ) cells in the elderly, while it had no effect on lymphocytes of the young group. Our results indicate that lymphocytes of the elderly population are characterized by a lower expression of the surface CD28 and CD152 molecules. An age-related decrease of an expression of the co-stimulatory molecules CD28 and CD152 on the surface of lymphocytes, found in our study, may be compatible with a hypothesis of a 'remodelling' of immune response in the healthy elderly.
MeSH Terms
- Abatacept
- Aged
- Aged, 80 and over
- Aging
- Antigens, CD
- Antigens, Differentiation
- CD28 Antigens
- CD8 Antigens
- CTLA-4 Antigen
- Cells, Cultured
- Female
- Flow Cytometry
- Humans
- Immunoconjugates
- Interleukin-2
- Lymphocyte Count
- Male
- T-Lymphocyte Subsets
Nonobese diabetic (NOD) mice spontaneously develop diabetes with a strong female prevalence; however, the mechanisms for this gender difference in susceptibility to T cell-mediated autoimmune diabetes are poorly understood. This investigation was initiated to find mechanisms by which sex hormones might affect the development of autoimmune diabetes in NOD mice. We examined the expression of IFN-gamma, a characteristic Th1 cytokine, and IL-4, a characteristic Th2 cytokine, in islet infiltrates of female and male NOD mice at various ages. We found that the most significant difference in cytokine production between sexes was during the early stages of insulitis at 4 wk of age. IFN-gamma was significantly higher in young females, whereas IL-4 was higher in young males. CD4( ) T cells isolated from lymph nodes of female mice and activated with anti-CD3 and anti-CD28 Abs produced more IFN-gamma, but less IL-4, as compared with males. Treatment of CD4( ) T cells with estrogen significantly increased, whereas testosterone treatment decreased the IL-12-induced production of IFN-gamma. We then examined whether the change in IL-12-induced IFN-gamma production by treatment with sex hormones was due to the regulation of STAT4 activation. We found that estrogen treatment increased the phosphorylation of STAT4 in IL-12-stimulated T cells. We conclude that the increased susceptibility of female NOD mice to the development of autoimmune diabetes could be due to the enhancement of the Th1 immune response through the increase of IL-12-induced STAT4 activation by estrogen.
MeSH Terms
- Aging
- Animals
- Cell Movement
- Cytokines
- DNA-Binding Proteins
- Diabetes Mellitus, Type 1
- Disease Susceptibility
- Down-Regulation
- Estrogens
- Female
- Interferon-gamma
- Interleukin-12
- Islets of Langerhans
- Male
- Mice
- Mice, Inbred C57BL
- Mice, Inbred NOD
- STAT4 Transcription Factor
- Sex Characteristics
- Signal Transduction
- T-Lymphocyte Subsets
- Testosterone
- Th1 Cells
- Th2 Cells
- Trans-Activators
- Up-Regulation
Telomere length is a good biomarker to study the cellular senescence as well as aging of an organism, because it regulates the replicative capacity of vertebrate somatic cells. To demonstrate age-related telomere length dynamics in the peripheral blood mononuclear cells (PBMC) of the cynomolgus monkey, we introduced a novel method of measuring telomere length by fluorescence in situ hybridization with a Peptide Nucleic Acid (PNA) labelled probe and flow cytometry (Flow FISH). A highly significant correlation was observed between the intensity of telomere-specific fluorescence by Flow FISH and telomere length by Southern blot analysis (R = 0.923, n = 22). The intensity of telomere fluorescence in PBMC significantly decreased with age in 55 monkeys aged from 0 to 34 years and this decrease corresponded to the loss of 62.7 base pairs per year (R = - 0.52, P < 0.00004). We also analysed the expression of naive cell-associated markers, CD28, CD62L and CD45RA/CD62L in T lymphocytes of 47 cynomolgus monkeys. An age-related increase in the CD28- subset was observed in CD8 T lymphocytes in monkeys less than 11 years old and in CD4 T lymphocytes in monkeys over 23 years old, respectively. The percentage of CD62L subsets was significantly decreased with age in both CD4 (R = - 0.55) and CD8 T lymphocytes (R = - 0.73). From the comparison of telomere length among PBMC, CD62L and CD62L- T lymphocytes, it was clearly evident that loss of naive subsets results in the shortening of telomere length in vivo. These results show that this method can be applicable to studying the turnover and precursor-progeny of PBMC in cynomolgus monkeys as an animal model of aging.
MeSH Terms
- Aging
- Animals
- CD28 Antigens
- CD4-Positive T-Lymphocytes
- CD8-Positive T-Lymphocytes
- Flow Cytometry
- In Situ Hybridization, Fluorescence
- L-Selectin
- Leukocyte Common Antigens
- Macaca fascicularis
- T-Lymphocyte Subsets
- Telomere
Immunosenescence is believed to contribute to increase susceptibility to infectious diseases and cancer in the elderly, and is caused mainly by changes in the T cell compartment. Longitudinal studies were undertaken to examine T cell surface receptor expression and apoptotic susceptibility using Staphylococcal enterotoxin B (SEB) activated human T cells as an in vitro model of an ageing T cell culture. An intracellular stain Carboxyfluorescein diacetate succinimidyl ester (CFSE) was used to assess the number of population divisions (PD) occurring in the ageing T cell culture. One major biomarker of aged T cells is a decrease in expression of CD28 and since this is an essential co-stimulatory molecule, its decreasing expression with age could compromise their activation and apoptotic capacity. Activation of T cells resulted in initial up-regulation of CD25, CD95 and CD28, although expression of CD25 and CD28 subsequently decreased with increasing PD. CD4 and CD8 T cells expressed similar CD25 profiles although CD28 expression was unique in each subset. CD4 cells expressed the highest CD28 levels, and showed a gradual decline in expression with increasing PD, whereas CD8 cells were low CD28 expressers, but did not appear to lose their expression as they aged. To determine T cell susceptibility to apoptosis via CD95/CD95-L interactions with increasing age, cells were challenged with CD95-L transfected CHO cells at various PD. Increased death was observed as they aged, which correlated with the decreased expression of activation markers CD25 and CD28.
MeSH Terms
- Adult
- Aging
- Animals
- Apoptosis
- CD28 Antigens
- CD4 Antigens
- CD4-Positive T-Lymphocytes
- CD8 Antigens
- CD8-Positive T-Lymphocytes
- CHO Cells
- Cells, Cultured
- Cellular Senescence
- Cricetinae
- Fluorescein-5-isothiocyanate
- Fluorescent Dyes
- Humans
- Longitudinal Studies
- Phycoerythrin
- Receptors, Interleukin-2
- Staining and Labeling
- Staphylococcus aureus
- T-Lymphocytes
- fas Receptor
Results from a previous longitudinal study, the Swedish OCTO-Immune study, indicated that the combination of higher CD8 peripheral blood lymphocytes (PBLs), decreased CD4 PBLs, and poor proliferative response to mitogenic stimulation in very old humans were associated with an increased 2 year mortality. In follow up studies this combination of immune parameters was significantly associated with a CD4/CD8 ratio less than one and positive IgG serologic titers to cytomegalovirus (CMV). The present study, the Swedish NONA-Immune study, was an extension of that study, using a new sample of the very old. The results of this study confirmed the results of the previous study and extended the surface marker profile of the PBLs, indicating that the CD4/CD8 ratio change is associated with increased CD8 cells, decreased CD4 cells, and lymphocyte activation. The predominant phenotypes of the CD3 CD8 cells were CD27-, CD28-, CD56 , and CD57 , CD45RA , and double marked CD45RA RO . As in the OCTO study, the NONA-Immune data indicated that the changes are associated significantly with seropositive responses to CMV.
MeSH Terms
- Adult
- Aged
- Aged, 80 and over
- Aging
- Antibodies, Viral
- Biomarkers
- CD3 Complex
- CD4-CD8 Ratio
- CD8-Positive T-Lymphocytes
- Carrier State
- Cytomegalovirus
- Cytomegalovirus Infections
- Female
- Humans
- Immunoglobulin G
- Lymphocyte Count
- Male
- Middle Aged
- Prevalence
- Sweden
- T-Lymphocyte Subsets
Recent reports from our laboratory have demonstrated that CD45RO and CD45RA T lymphocytes from the elderly are compromised in their response to activation-induced IL-2 receptor expression, IkappaB-alpha degradation, as well as nuclear translocation of NFkB. To understand the basis of this activation-induced dysfunction in the elderly, we have examined the role of the ubiquitin-proteasome pathway. Our results demonstrate that both CD45RO and CD45RA T lymphocytes from the elderly show significant reduction in the constitutive 26S proteasome-associated chymotryptic activity, when compared to those in the young. Additionally, anti-CD3-CD28 treatment induced enhancement of proteasome-associated enzymatic activity in cells from the young, but not in cells from the elderly. Lowered proteasome-associated activity and its effect on reduced immune responses in the elderly could be mimicked by experiments which involved pretreatment of T cells from young donors with a proteasome specific inhibitor, lactacystin. These data demonstrate that IL-2 receptor induction is clearly compromised in T cells from the young when proteasomes are inhibited by pretreatment with lactacystin. An examination of ubiquitin specific hydrolase activity, demonstrated a decrease in activated CD45RA and CD45RO T cell subsets from the elderly when compared to young. These results suggest that lowered proteasome-associated enzymatic activity in combination with compromised de-ubiquitinating activity may be responsible for lowered activation-induced NFkB and NFkB-mediated gene expression in elderly subjects.
MeSH Terms
- Acetylcysteine
- Adult
- Aged
- Aged, 80 and over
- Aging
- Biomarkers
- CD28 Antigens
- CD3 Complex
- Chymotrypsin
- Cysteine Endopeptidases
- Cysteine Proteinase Inhibitors
- Female
- Humans
- Leukocyte Common Antigens
- Lymphocyte Activation
- Male
- Multienzyme Complexes
- Peptide Hydrolases
- Proteasome Endopeptidase Complex
- Receptors, Interleukin-2
- Signal Transduction
- T-Lymphocyte Subsets
- Ubiquitin
T cells from HIV and aged individuals show parallels in terms of suppressed proliferative activity and interleukin-2 (I1-2) production and an increased number of CD8 CD28- T cells. In order to compare cytokine production from T cells from these two states, CD4 and CD8 T cells from HIV aged, and normal young donors (controls) were monitored for cytokine production by flow cytometry, quantitative PCR and ELISA upon activation by PMA and anti-CD3. In addition, the CD8 T cell subsets CD28 and CD28- from the HIV and the aged groups were evaluated for cytokine production by flow cytometry, and compared with those from young controls. Flow cytometric analysis indicated that CD8 T cells from both HIV and aged donors showed an increase of approximately 2-3 fold over controls in percentage of cells producing inflammatory cytokines IFN-gamma and TNF-alpha. Similar analysis also revealed that the production of interleukins-4,6 and 10, production was very low (1-2% of cells) and unchanged in these cells. Quantitative PCR also showed a substantial increase (4-5 fold) in IFN-gamma and TNF-alpha mRNA from HIV and aged CD8 T cells, as did ELISA for secreted IFN-gamma and TNF-alpha (2.3-4 fold). Flow cytometric analysis showed that the CD8 CD28- T cell subset accounts for approximately 80-86% of the IFN-gamma and TNF-alpha production from the CD8 subset in the aged and HIV states. The CD4 T cell, while not significantly changed in the HIV or aged states in terms of IFN-gamma production, showed a small but significant increase in TNF-alpha production in both states. Our data appear compatible with physiologic conditions existing in HIV and aged individuals, i.e. elevated serum levels and elevated CD8 T cell production of IFN-gamma and TNF-alpha. Thus, the capacity for increased production of cytokines IFN-gamma and TNF-alpha in the aged individual by the dominant CD8 CD28- subset may have a profound influence on the clinical state by aggravating inflammatory pathologies such as rheumatoid arthritis, and possibly Alzheimer's disease and Crohn's disease. In AIDS, these cytokines may contribute to wasting and cachexia. We theorize that the predominant phenotypic change to the cytotoxic CD8 CD28- T cell subsets in both the HIV and the aged states may reflect a natural "endpoint" in CD8 T cell differentiation induced after a lifetime of immune activity (toward viruses, etc) in the aged, and after a massive accelerated response to HIV in the HIV-positive individual.
MeSH Terms
- Adult
- Aged
- Aging
- CD28 Antigens
- CD8-Positive T-Lymphocytes
- Cytokines
- Enzyme-Linked Immunosorbent Assay
- Flow Cytometry
- HIV Infections
- Humans
- Interferons
- RNA, Messenger
- T-Lymphocytes
- Transcription, Genetic
- Tumor Necrosis Factor-alpha
Aging and chronic inflammatory syndromes, such as rheumatoid arthritis, are associated with high frequencies of CD4( )CD28(null) T cells, which are rarely seen in healthy individuals younger than 40 years. Inasmuch as rheumatoid arthritis and aging are also associated with elevated levels of TNF-alpha, we examined whether this proinflammatory cytokine influences CD28 expression. Incubation of T cell lines and clones as well as Jurkat cells with TNF-alpha induced a reduction in the levels of cell surface expression of CD28. This effect of TNF-alpha was reversible; however, continuous culture of CD4( )CD28( ) T cell clones in TNF-alpha resulted in the appearance of a CD28(null) subset. In reporter gene bioassays, TNF-alpha was found to inhibit the activity of the CD28 minimal promoter. Inactivation of the promoter was accompanied by a marked reduction in DNA-protein complex formation by two DNA sequence motifs corresponding to the transcriptional initiator of the CD28 gene. Indeed, in vitro transcription assays showed that nuclear extracts from TNF-alpha-treated cells failed to activate transcription of DNA templates under the control of a consensus TATA box and the CD28 initiator sequences. In contrast, similar extracts from unstimulated T cells supported transcription. These results demonstrate that TNF-alpha directly influences CD28 gene transcription. We propose that the emergence of CD4( )CD28(null) T cells in vivo is facilitated by increased production of TNF-alpha.
MeSH Terms
- Aging
- Annexin A5
- Apoptosis
- Arthritis, Rheumatoid
- CD28 Antigens
- CD4-Positive T-Lymphocytes
- Camptothecin
- Cell Line
- Cell-Free System
- Clone Cells
- Down-Regulation
- Genes, Reporter
- Humans
- Jurkat Cells
- Lymphocyte Activation
- Neoplasm Proteins
- Promoter Regions, Genetic
- RNA, Messenger
- RNA, Neoplasm
- T-Lymphocytes
- TATA Box
- Transcription, Genetic
- Tumor Necrosis Factor-alpha
While the T-cell receptor (TCR) repertoire of the newborn is highly diverse, a gradual alteration in diversity of the expressed TCR repertoire, in particular the oligoclonality of CD8 T cells, occurs with increasing age. The timing of the initiation of this process is unknown. These changes are associated with an accumulation of T-cell expansions, thought to be in response to chronic antigen stimulation, frequently by persistent viruses such as Epstein-Barr virus (EBV) and cytomegalovirus (CMV). Using reverse transcription-polymerase chain reaction heteroduplex analysis we have characterized the TCR expression of CD4 and CD8 cells from healthy young children and adults in order to delineate the age range at which these oligoclonal populations appear. We demonstrate that considerable oligoclonality can occur, even in healthy young children, and also that these expanded clonotypes persist. These are shown by heteroduplex to be exclusively within the CD28- subpopulation. The presence of such oligoclonal expansions correlates closely with the percentage of CD8 cells that have the CD28- phenotype. However, we also show that control of chronic infection with EBV or CMV may coexist with a highly diverse, polyclonal TCR repertoire well into adulthood. These studies suggest that many factors affect the overall regulation of clone size in response to chronic antigens during the development of the immune system.
MeSH Terms
- Adolescent
- Adult
- Aging
- CD28 Antigens
- CD8-Positive T-Lymphocytes
- Child
- Child, Preschool
- Chronic Disease
- Clone Cells
- Cytomegalovirus Infections
- Epstein-Barr Virus Infections
- Flow Cytometry
- Humans
- Immunophenotyping
- Infant
- Receptors, Antigen, T-Cell
- Reverse Transcriptase Polymerase Chain Reaction
- T-Lymphocyte Subsets
In humans, CD56, CD161, CD16, CD94 or CD57 represent prototypic markers of NK cells, although they are also found on a subset of CD8 T cells. We propose here that the expression of NK receptors on CD8 T cells can be considered a marker of cytotoxic effector T cells that are expanded in vivo after antigenic activation leading to extensive proliferation. The persistence of antigen will lead to loss of co-stimulatory molecules, telomere shortening and defective IL-2 production, changes that define the state replicative senescence in T lymphocytes. The majority of these "effector/senescent" T lymphocytes are CD8 , CD45RA , CD11a(bright), CD28-, CD27-, CD62L- and CCR7-. They are cytotoxic T cells with strong expression of intracytoplasmic perforin and granzyme, but with low proliferative capacity and defective IL-2 production. Many of these characteristics are shared by the recently defined "effector/memory" T cells, being mainly distinguished by the absence of CD45RA expression on the memory cells. The expression of NK receptor in these effector cells will probably contribute to the regulation of their cytotoxic function. Expansion of cells with these characteristics can be found not only in the elderly but also in other clinical conditions involving chronic activation of the immune system such as viral infections, rheumatic and autoimmune diseases or tumors. Another subset of T cells that expresses the NK receptors is the alpha-galactosyl-ceramide specific T cell subset defined by the expression of canonical Valpha24JalphaQ TCR, recognition of CD1d and secretion of high amounts of IL-4 and IFN-gamma. However, the changes observed in the expression of NK-R on T cells associated to immunosenescence can not be attributed to expansion of this particular T cell subset, although alterations in the number and function of these cells have been demonstrated in some autoimmune diseases.
MeSH Terms
- Aging
- Biomarkers
- Cellular Senescence
- Humans
- Immune System
- Killer Cells, Natural
- T-Lymphocytes, Cytotoxic
- T-Lymphocytes, Regulatory
To characterize early and later indices of cellular restoration among HIV-1 infected persons treated with abacavir and one protease inhibitor and to identify predictors of CD4 cell increases. Flow-cytometric analyses of lymphocyte phenotypes among 71 antiretroviral treatment naive adults in a 48 week treatment trial. During the first 4 weeks of therapy, increases in naive and memory CD4 cells and in B cells were seen; naive CD8 cells increased while CD8 cells remained stable as memory CD8 cells decreased. During the second phase total CD4 and naive CD4 and CD8 cells increased while total CD8 and memory CD8 cells decreased. The numbers of CD4 cells that expressed CD28 increased from a median of 308 x 10(6)/l at baseline to 477 x 10(6)/l at week 48. Higher baseline plasma HIV-1 RNA levels predicted the magnitude of early CD4 (r = 0.35; P = 0.01), memory CD4 (r = 0.38; P = 0.001) and CD28 CD4 cell (r = 0.29; P = 0.01) restoration but was not related to second phase changes. Younger age predicted a greater second phase (but not first phase) increase in naive CD4 cells (r = -0.31; P = 0.03). Higher baseline levels of HIV-1 replication determine the magnitude of first phase CD4 cell increases after suppression of HIV-1 replication. Second phase (primarily naive) CD4 cell increases are not related to HIV-1 replication but are inversely relate to age suggesting that thymic potential is a major determinant of long term cellular restoration in HIV-1 infected persons receiving antiretroviral therapy.
MeSH Terms
- Adolescent
- Adult
- Aged
- Aging
- Antigens, CD
- CD4 Lymphocyte Count
- CD4-Positive T-Lymphocytes
- CD8-Positive T-Lymphocytes
- Dideoxynucleosides
- Drug Therapy, Combination
- Female
- Flow Cytometry
- HIV Infections
- HIV Protease Inhibitors
- HIV-1
- Humans
- Immunologic Memory
- Immunophenotyping
- Male
- Middle Aged
- RNA, Viral
- Reverse Transcriptase Inhibitors
Since CD28 costimulation is critical for T-cell activation, there is great interest in CD28 as a target for immuntherapeutic approaches. We show that stimulation of human CD4( ) and CD8( ) T-cells differs in their responsiveness to stimulation with anti-CD3/CD28-coated beads, as surrogate antigen-presenting cells. While the CD4( ) subset responded with sustained proliferation, CD8( ) T-cells grew for a limited period only and failed to produce IL-2 beyond the first few days in culture. This decrease is accompanied with an increased rate of apoptosis in CD8( ) T-cells despite Bcl-x(L) expression. The CD8( ) but not the CD4( ) subset developed a reversible double-positive phenotype during CD28 costimulation. This finding may have some bearing on the appearance of double-positive T-cells in human peripheral blood. This double-positive subset was shown to undergo a statistically significantly increase during aging in humans. Taken together, the above data have important implications for immunotherapy and immune senescence.
MeSH Terms
- Adult
- Aged
- Aged, 80 and over
- Aging
- CD28 Antigens
- CD4-Positive T-Lymphocytes
- CD8-Positive T-Lymphocytes
- HLA-DP Antigens
- Humans
- Immunotherapy, Adoptive
- Lymphocyte Activation
- Phenotype
Aging is associated with a decline in immune function. Interferon-gamma (IFN-gamma) and interleukin-4 (IL-4), two important immune deviation-related cytokines, are mainly produced by type 1 and type 2 T cells, respectively. To investigate the age-associated changes in the secretion of these two cytokines, 20 elderly and 20 young subjects fulfilling the SENIEUR protocol were enrolled. The ratios of CD4 to CD8 T cells were not different between the two age groups. The CD4 and CD8 T cells were purified by a magnetic cell sorting system, and then activated by concurrent anti-CD3 and anti-CD28 stimulation. The released cytokines were determined by ELISA. Both the CD4 and the CD8 T cells of the elderly individuals secreted a significantly larger amount of IFN-gamma after activation. Profound IL-4 production by CD8 T cells was observed in the older subjects compared with that of the young subjects. These data suggested that age-associated decrease in immunity may be related to an imbalance in the secretion of immune deviation cytokines. The number of IL-4-secreting CD8 T cells (T cytotoxic 2) rose significantly in the older individuals. Our design also provided a useful way to differentiate the T cell subsets secreting the same cytokine, such as IFN-gamma-producing T helper 1 and T cytotoxic 1 cells.
MeSH Terms
- Adolescent
- Adult
- Aged
- Aging
- CD4-CD8 Ratio
- CD4-Positive T-Lymphocytes
- CD8-Positive T-Lymphocytes
- Cells, Cultured
- Enzyme-Linked Immunosorbent Assay
- Female
- Flow Cytometry
- Humans
- Interferon-gamma
- Interleukin-4
- Lymphocyte Activation
- Male
Immune changes and their relationships in a frail elderly population (N=116, age 70-103, median 86 years) were defined in comparison to a healthy younger group. Previous immune studies in the elderly have generally focused on one or few parameters without correlation analyses. Furthermore, the study populations have been active elderly in relatively small numbers. A total of 33 immune parameters representing many aspects of the immune system were quantified. Most changes in the frail elderly were parallel to those reported in active elderly. A classification tree analysis revealed that increased plasma activation markers (neopterin and sTNF-R) and increased CD28 expression on CD8 T cells and proliferative response separated the aged and control populations. Statistical procedures utilizing principal components analyses, partial correlations and exploratory factor analyses all indicated that immunologic parameters in frail elderly are grouped in three major clusters of immunologic results. These involved (a) increased plasma levels of neopterin and sTNF receptor indicating elevated IFNgamma and TNF cytokine activity; (b) increased proportion of mature (CD45RO) versus naïve (CD45RA) T cells; and (c) a diverse group of related changes including impaired proliferative response, reduced T cells, CD28 and CD25 expression, B cell percentage and lower CD4:CD8 ratios and increased HLA-DR expression. These findings emphasize that several different groups of immune parameters but not 33 independent immune changes, occurred in the aged population.
MeSH Terms
- ADP-ribosyl Cyclase
- ADP-ribosyl Cyclase 1
- Adult
- Aged
- Aged, 80 and over
- Aging
- Antigens, CD
- Antigens, Differentiation
- CD28 Antigens
- Cell Division
- Cytokines
- Female
- Frail Elderly
- HLA-DR Antigens
- Humans
- Immune System
- Immunologic Memory
- Lymphocyte Subsets
- Male
- Membrane Glycoproteins
- Middle Aged
- NAD Nucleosidase
- Phenotype
- Reference Values
- T-Lymphocytes
The human immune system undergoes continuous remodelling with the advancement of age. Since age-associated functional alterations in the immune system could be caused by a possible change in helper T cell regulation in elderly subjects, we comparatively studied the function of CD4 T cells in peripheral blood obtained from both young and old healthy volunteers. Upon cell activation by phorbol myristate acetate and ionomycin, the proportion of CD4 T cells containing interferon-gamma (IFN-gamma) was found to be greater in the old subjects. Utilizing a co-culture system, which activated CD4 T cells via the TCR/CD3 complex and CD28, we found that CD4 T cells from the old subjects secreted more IFN-gamma and IL-2, but less IL-4, than those from the young subjects. Upon cell activation by co-culture, CD4 T cells from the old subjects expressed more CD26, CD40L, and LFA-1, but less CD30, than those from the young. These results together suggest that the microenvironment in which CD4 T cells develop in older people may cause production of more cells committed to Th1 than that in younger subjects.
MeSH Terms
- Adolescent
- Adult
- Aged
- Aging
- B7-1 Antigen
- CD3 Complex
- CD4-Positive T-Lymphocytes
- CD40 Ligand
- Cells, Cultured
- Dipeptidyl Peptidase 4
- Humans
- Interferon-gamma
- Interleukin-2
- Interleukin-4
- Intracellular Fluid
- Ionomycin
- Ki-1 Antigen
- Leukocyte Common Antigens
- Lymphocyte Function-Associated Antigen-1
- Membrane Glycoproteins
- Middle Aged
- Mitogens
- Tetradecanoylphorbol Acetate
- Th1 Cells
- Th2 Cells
Clinical observations indicate that elderly people are prone to severe, often lethal infectious diseases induced by novel pathogens. Since the ability to mount primary immune responses relies on the availability of naive T cells, the circulating naive T-cell reservoir was evaluated throughout the human life span. Naive T cells were identified as CD95(-) T lymphocytes for their phenotypic and functional features. Indeed, the lack of CD95 marker is sufficient to identify a population of naive T cells, as defined by coincidence with previously characterized CD45RA( ) CD62L( ) T cells. Naive CD95(-) T cells, as expected, require a costimulatory signal, such as CD28, to optimally proliferate after anti-CD3 stimulation. Cytofluorimetric analysis of circulating T lymphocytes from 120 healthy subjects ranging in age from 18 to 105 years revealed that naive T cells decreased sharply with age. The younger subjects had a naive T-lymphocyte count of 825 /- 48 cells/microL, and the centenarians had a naive T-lymphocyte count of 177 /- 28 cells/microL. Surprisingly, the naive T-cell count was lower in CD8( ) than in CD4( ) subsets at any age, and the oldest individuals were almost completely depleted of circulating naive CD8( ) T cells (13 /- 4 cells/microL). Concomitantly, a progressive expansion of CD28(-) T cells occurs with age, which can be interpreted as a compensatory mechanism. These data provide new insights into age-related T-cell-mediated immunodeficiency and reveal some analogies of T-cell dynamics between advanced aging and human immunodeficiency virus (HIV) infection. In conclusion, the exhaustion of the naive CD8( ) T-cell reservoir, which has never been reported before, suggests that this T-cell pool is a major target of the aging process and may define a parameter possibly related to the life span of humans. (Blood. 2000;95:2860-2868)
MeSH Terms
- Adolescent
- Adult
- Aged
- Aged, 80 and over
- Aging
- Antigens, CD
- CD4 Lymphocyte Count
- CD8-Positive T-Lymphocytes
- Humans
- Immunologic Deficiency Syndromes
- L-Selectin
- Leukocyte Common Antigens
- Lymphocyte Activation
- Lymphocyte Count
- Middle Aged
- Regression Analysis
- T-Lymphocytes
Aging is associated with the progressive increase of T cells that lack expression of the CD28 costimulatory molecule. Because CD28/B7 signal transduction is required for proliferation, T cells lacking CD28 gene expression are incapable of clonal expansion. To determine whether CD28- T cells are a separate lineage or, alternatively, are the progeny of formerly CD28 T cells, we performed cell culture longitudinal analysis on the same population of T cells over time. Repeated antigen-induced T cell division ultimately leads to irreversible cell cycle arrest, shortened telomeres, loss of telomerase inducibility, and total absence of expression of CD28. This in vitro model has elucidated a novel facet of T cell biology that may explain the increased incidence of infection and cancer in the elderly.
MeSH Terms
- Aging
- CD28 Antigens
- CD8-Positive T-Lymphocytes
- Cell Division
- Cells, Cultured
- Cellular Senescence
- Humans
- Lymphocyte Activation
- Models, Biological
- T-Lymphocytes
- Telomerase
c-Jun N-terminal kinase (JNK) is activated when T-lymphocytes are stimulated jointly through the T-cell receptor (TCR) and CD28, and it contributes to T-cell activation and IL-2 production through phosphorylation of transcription factors, including c-Jun. We performed in vitro kinase assays on JNK in CD4( ) T-cells, from young and old mice, activated by antibodies to CD3, CD4, and CD28, and found a approximately 2-fold decline in JNK activity at the peak of activation, but no significant change in the kinetics of stimulation or in the steady-state expression of JNK. We found a similar decline in c-Jun phosphorylation in stimulated CD4( ) T-cells from old mice, suggesting that JNK activation also declined with age in intact cells. Aging does not, however, alter the level of Ras activation by anti-CD3/CD4 /- anti-CD28 or change the level of Ras protein in CD4( ) cells, suggesting that the JNK defect is due to changes in the regulation of other upstream regulators. Our results suggest that a decline with age in JNK responses may contribute to the decline in proliferation and IL-2 production seen in CD4( ) T-cells from old mice.
MeSH Terms
- Aging
- Animals
- CD28 Antigens
- CD3 Complex
- CD4 Antigens
- CD4-Positive T-Lymphocytes
- Cells, Cultured
- Enzyme Activation
- Humans
- JNK Mitogen-Activated Protein Kinases
- Jurkat Cells
- Male
- Mice
- Mice, Inbred BALB C
- Mice, Inbred C57BL
- Mitogen-Activated Protein Kinases
- Mitogens
- Phosphorylation
- Signal Transduction
- ras Proteins
This study was performed in order to investigate the type of T cells recruited to the blood in response to an acute bout of exercise with regard to mean lengths of telomeric terminal restriction fragments (TRF) and surface activation markers and with special emphasis on age-associated differences. Ten elderly and ten young humans performed maximal bicycle exercise. There was no difference in the number of recruited CD4 and CD8 cells between the young and elderly group. In both age groups the immediate increases could be ascribed to recruitment of CD28- cells (CD8 and CD4 cells) and memory cells (only CD8 cells). Furthermore, after exercise mean TRF lengths were significantly reduced in blood mononuclear cells and in CD8 cells from young subjects and in CD4 cells from elderly subjects compared with lengths pre-exercise. These findings suggest that the mobilization of T lymphocytes during acute exercise is mainly a redistribution of previously activated cells with an increased replicative story than cells isolated from the blood at rest. Furthermore, elderly humans fulfilling the Senieur protocol have a preserved ability to recruit T lymphocytes in response to acute physical stress.
MeSH Terms
- Adult
- Aged
- Aged, 80 and over
- Aging
- CD28 Antigens
- CD4-CD8 Ratio
- Catecholamines
- Female
- Heart Rate
- Humans
- Immunophenotyping
- Leukocytes, Mononuclear
- Lymphocyte Activation
- Male
- Oxygen Consumption
- Physical Exertion
- T-Lymphocyte Subsets
- Telomere
The c-Jun N-terminal kinase (JNK) can be activated in T-cells either by the combination of TCR and CD28 costimulation or by a variety of stress-related stimuli including UV light, H(2)O(2), and hyperosmolar sorbitol solutions. In T-lymphocytes, TCR/CD28 stimulation of JNK leads to induction of new gene expression via c-Jun, ATF-2, and Elk-1. Phosphorylation of c-Jun in CD4( ) T-cells stimulated by CD3/CD4/CD28 cross-linking declines with age, due to diminished activation of JNK. Here we show that the age-related decline in TCR/CD28 activation of JNK reflects two effects of age: the accumulation of memory cells (in which JNK stimulation is poor regardless of donor age) and age-dependent declines in JNK activation within the naive subset. Cyclosporin A inhibits induction of JNK function by TCR/CD28, PMA/ionomycin, ceramide, or H(2)O(2), but not induction by UV light or hyperosmolar sorbitol. Although aging impairs JNK induction by UV light, it has no effect on JNK activation by ceramide, H(2)O(2), or sorbitol. The data as a whole indicate that there are at least four pathways that activate JNK in CD4( ) T-cells, of which two are age-sensitive and two others unaffected by aging. Two of the pathways (UV and hyperosmolar sorbitol) are insensitive to cyclosporin inhibition. Finally, we show that the alterations in JNK function are not due to changes in the expression of MKK4, an upstream activator of JNK, and that another JNK kinase, MKK7, is not expressed in splenic T-cells.
MeSH Terms
- Aging
- Animals
- CD4-Positive T-Lymphocytes
- Cells, Cultured
- Ceramides
- Colforsin
- Cyclosporine
- Dimethyl Sulfoxide
- Enzyme Activation
- Humans
- Hydrogen Peroxide
- Immunologic Memory
- JNK Mitogen-Activated Protein Kinases
- Jurkat Cells
- MAP Kinase Kinase 4
- MAP Kinase Kinase 7
- MAP Kinase Signaling System
- Mice
- Mice, Inbred BALB C
- Mice, Inbred C57BL
- Mitogen-Activated Protein Kinase Kinases
- Mitogen-Activated Protein Kinases
- Protein-Tyrosine Kinases
- Sorbitol
- Ultraviolet Rays
To define the link between the early activation defects and the impaired proliferation response of cells from old mice, we characterized the influence of age on expression and activity of proteins that participate in cell-cycle regulation. We found that aging led to significant declines in the ability of mouse CD4( ) T cells to respond to CD3 and CD28 stimuli by induction of the cyclin-dependent kinases CDK2, CDK4, and CDK6, whether the defect was assessed by protein level or functional activity. Induction of CDK2 activity was also impaired in cells from old mice that were activated with PMA plus ionomycin, stimuli that bypass the TCR/CD3 complex, or by CD3/CD28 in the presence of IL-2, indicating that the age-related changes lie, at least in part, downstream of the enzymes activated by these stimuli. We also noted an impairment in the ability of CD4( ) cells from old mice to down-regulate the CDK inhibitor p27 after activation, but we found no change in induction of p21, an inhibitor of CDK that may also play other roles in cell-cycle control. Altered CDK activation is likely to mediate the age-related decline in T cell proliferation to polyclonal stimulation.
MeSH Terms
- Aging
- Animals
- Blood Platelets
- CD28 Antigens
- CD3 Complex
- CD4-Positive T-Lymphocytes
- CDC2-CDC28 Kinases
- Cell Cycle Proteins
- Cyclin-Dependent Kinase 2
- Cyclin-Dependent Kinase 4
- Cyclin-Dependent Kinase 6
- Cyclin-Dependent Kinase Inhibitor p27
- Cyclin-Dependent Kinases
- Down-Regulation
- Enzyme Activation
- Enzyme Induction
- Enzyme Inhibitors
- Interleukin-2
- Isoantibodies
- Kinetics
- Lymphocyte Activation
- Mice
- Mice, Inbred BALB C
- Mice, Inbred C57BL
- Microtubule-Associated Proteins
- Protein-Serine-Threonine Kinases
- Proto-Oncogene Proteins
- Tetradecanoylphorbol Acetate
- Tumor Suppressor Proteins
Spleen cells from young and old C57BL/6 mice were stimulated with a combination of anti-CD3 and anti-CD28 antibodies, and the profile of cytokine production was examined by two different methods; the concentrations of cytokines as measured by ELISA, and identification of cytokine-positive cells by flow cytometry. The ELISA method revealed that IL-2 production by spleen cells after stimulation was significantly lower in the old mice compared to the young mice. while IFN-gamma production was the reverse. The flow cytometric analysis showed that the percentage of IL-2 positive cells in spleen cells after the stimulation was significantly lower in the older mice than in the young mice, and vice versa for the percentage of IFN-gamma-positive cells. Regarding the T cell subsets, CD4 T cells were a major source of IL-2 in both the young and old mice. IL-2-positive cells in both CD4 and CD8 T cells showed a significant decrease with age. On the contrary, CDX T cells were the major source of IFN-gamma. An age-related increase of IFN-gamma positive cells was observed in both CD4 and CD8 T cells. CD4 T cells were the major source of IL-4, and the percentage of IL-4-positive CD4 T cells also increased with age, although the level of IL-4 production was modest in C57BL/6 mice compared with IL-2 and IFN-gamma. Such age-related changes of cytokine production are presumed to play an important role in the alteration of immunological capacity with age.
MeSH Terms
- Aging
- Animals
- Antibodies, Monoclonal
- CD28 Antigens
- CD3 Complex
- CD4-Positive T-Lymphocytes
- CD8-Positive T-Lymphocytes
- Cytokines
- Enzyme-Linked Immunosorbent Assay
- Flow Cytometry
- In Vitro Techniques
- Interferon-gamma
- Interleukin-2
- Interleukin-4
- Lymphocyte Activation
- Mice
- Mice, Inbred C57BL
- Spleen
- T-Lymphocyte Subsets
the antigen CD28, expressed in most T cells, has co-stimulatory properties and plays a pivotal role in clonal T cell anergy mechanisms. we have compared proliferative T cell responses after anti-CD3 or in phorbol myristate acetate activation with concomitant CD28 signal in peripheral blood mononuclear cells from healthy donors aged over 65 [elderly donors; ED] and young healthy donors (YD); mean age 30 /-2.7 years). no proliferative responses were observed in ED and YD with anti-CD28 monoclonal antibody alone. These responses both were defective in ED, particularly after anti-CD3 monoclonal antibody stimulus (7604 compared with 12,438 c.p.m. in YD, P=0.001) and were corrected when anti-CD28 monoclonal antibody was added to the culture (17,216 vs 18,536, not significant). Functional integrity of the CD28 co-stimulatory pathway was demonstrated by analysis of CD25 expression, interleukin-2 secretion and interleukin-2 gene expression on T cells from ED and YD. Age-associated phenotypic T cell changes were not crucial for an adequate CD28 response. these experiments demonstrate the integrity of the CD28 pathway in elderly people, and suggest that ageing does not affect different T cell activation pathways equally.
MeSH Terms
- Adult
- Aged
- Aging
- CD28 Antigens
- Cell Division
- Female
- Humans
- Immunophenotyping
- Interleukin-2
- Male
- Mitogens
- Receptors, Interleukin-2
- Signal Transduction
- T-Lymphocytes
- Tetradecanoylphorbol Acetate
- Transcription, Genetic
Current antiretroviral treatment can induce significant and sustained virological and immunological responses in HIV-1-infected persons over at least the short- to mid-term. In this study, long-term immune reconstitution was investigated during highly active antiretroviral therapy. Patients enrolled in the INCAS study in The Netherlands were treated for 102 weeks (range 52-144 weeks) with nevirapine (NVP) zidovudine (ZDV) (n = 9), didanosine (ddl) ZDV (n = 10), or NVP ddl ZDV (n = 10). Memory and naïve CD4 and CD8 T cells were measured using CD45RA and CD27 monoclonal antibodies (mAb), T-cell function was assayed by CD3 CD28 mAb stimulation, and plasma HIV-1 RNA load was measured by ultra-direct assay (cut-off < 20 copies/ml). Compared to both double combination regimens the triple combination regimen resulted in the most sustained increase in CD4 T cells (change in CD4 , 253 x 10(6) cells/l; standard error, 79 x 10(6) cells/l) and reduction of plasma HIV-1 RNA. In nine patients (31%) (ddl ZDV, n = 2; NVP ddl ZDV, n = 7) plasma HIV-1 RNA levels remained below cut-off for at least 2 years. On average, these long-term virological responders demonstrated a significantly higher increase of naïve and memory CD4 T cells (P = 0.01 and 0.02, respectively) as compared with patients with a virological failure, and showed improved T-cell function and normalization of the naïve; memory CD8 T-cell ratio. However, individual virological success or failure did not predict the degree of immunological response. T-cell patterns were independent of baseline CD4 T-cell count, T-cell function, HIV-1 RNA load or age. Low numbers of naïve CD4 T cells at baseline resulted in modest long-term naïve T-cell recovery. Patients with prolonged undetectable plasma HIV-1 RNA levels during antiretroviral therapy do not invariably show immune restoration. Naïve T-cell recovery in the setting of complete viral suppression is a gradual process, similar to that reported for immune recovery in adults after chemotherapy and bone marrow transplantation.
MeSH Terms
- Adult
- Aging
- Anti-HIV Agents
- Didanosine
- Follow-Up Studies
- HIV Infections
- HIV-1
- Humans
- Immunologic Memory
- Middle Aged
- Nevirapine
- Reverse Transcriptase Inhibitors
- Time Factors
- Zidovudine
During human aging, one of the major changes in the T cell repertoire is a dramatic expansion of T cells with the atypical CD28-CD8 phenotype. In this study, we show that this increase is a consequence not only of an expansion in the CD28-CD8 population but also of a decrease in the number of CD28 CD8 T cells. The decrease in circulating CD28 CD8 T cells is dramatically accelerated after the age of 50 and is not accompanied by an equivalent reduction in the CD28 CD8 subset. Our findings confirm that aging leads to an accumulation of CD45RO T cells within the CD28 CD8 subset as previously observed. Surprisingly, we found an increase in CD45RA expression with age in the CD28-CD8 subset. Immune-phenotyping for activation markers, measurement of telomere DNA content, and cytokine production analysis indicate that the large majority of CD28-CD8 T cells are Ag-experienced, despite their CD45RA phenotype. Our study further demonstrates that the poor proliferative response displayed by CD28-CD8 T cells is not a consequence of telomere shortening. Also, analysis of cytokine production at the single cell level revealed that the proportions of IFN-gamma , IL-4 , and IL-10 T cells are considerably higher among the CD28-CD8 than the CD28 CD8 subset. In summary, these data explain the presence of CD45RA T cells in the elderly, shed light on the phylogenetic origin of CD28-CD8 T cells, and suggest a role for these cells in the immune senescence process.
MeSH Terms
- Adolescent
- Adult
- Aged
- Aged, 80 and over
- Aging
- CD28 Antigens
- CD4-CD8 Ratio
- CD4-Positive T-Lymphocytes
- CD8 Antigens
- CD8-Positive T-Lymphocytes
- DNA
- Humans
- Immunologic Memory
- Immunophenotyping
- Interphase
- Leukocyte Common Antigens
- Middle Aged
- T-Lymphocyte Subsets
- Telomere
- Thymus Gland
The effect of prior cytomegalovirus (CMV) infection on the immune system was evaluated in young and elderly volunteers. Prevalence of IgG antibodies to CMV was higher in the elderly volunteers. In both age groups, there was a strong association with CMV seropositivity and increased number of CD28- CD4 or CD8 T cells, as well as with increased numbers of T cells expressing CD56 or DR. Although these changes have previously been reported to be age-related, they were independent of age when CMV serological status was taken into account. In contrast, both age group and CMV status were important determinants of the total number of T cells, the number of CD8 T cells, and the number of CD8 T cells expressing CD45RA or CD28. These findings indicate that prior infection with CMV, as reflected by CMV serological status, has important effects on T cell subsets and surface markers and must be considered whenever evaluating age-related changes in immunological parameters.
MeSH Terms
- Adult
- Aged
- Aged, 80 and over
- Aging
- Antibodies, Viral
- CD28 Antigens
- CD4-Positive T-Lymphocytes
- CD56 Antigen
- CD8-Positive T-Lymphocytes
- Cytomegalovirus
- Cytomegalovirus Infections
- HLA-DR Antigens
- Humans
- Immunoglobulin G
- Leukocyte Common Antigens
- T-Lymphocyte Subsets
- T-Lymphocytes
CD8 T cells contain a distinct subset of CD8 CD28- cells. These cells are not present at birth and their frequency increases with age. They frequently contain expanded clones using various TCRalphabeta receptors and these clones can represent >50% of all CD8 cells, specially in old subjects or patients with chronic viral infections such as HIV-1. Herein, it is shown that a large fraction of CD8 CD28- cells expresses intracellular perforin by three-color flow cytometry, in particular when this subset is expanded. Together with their known ability to exert potent re-directed cytotoxicity, this indicates that CD8 CD28- T cells comprise cytotoxic effector cells. With BrdU labeling, we show that CD8 CD28- cells derive from CD8 CD28 precursors in vitro. In addition, sorted CD8 CD28 cells gave rise to a population of CD8 CD28- cells after allo-stimulation. Moreover, ex vivo CD8 CD28 cells contain the majority of CD8 blasts, supporting the notion that they contain the proliferative precursors of CD8 CD28- cells. CD95 (Fas) expression was lower in CD8 CD28- cells, and this subset was less prone to spontaneous apoptosis in ex vivo samples and more resistant to activation-induced cell death induced by a superantigen in vitro. Thus, the persistence of expanded clones in vivo in the CD8 CD28- subset may be explained by antigen-driven differentiation from CD8 CD28 memory precursors, with relative resistance to apoptosis as the clones become perforin( ) effector cells.
MeSH Terms
- Adult
- Aged
- Aging
- Apoptosis
- CD28 Antigens
- CD8-Positive T-Lymphocytes
- Cell Differentiation
- Clone Cells
- Humans
- Membrane Glycoproteins
- Middle Aged
- Perforin
- Pore Forming Cytotoxic Proteins
- Receptors, Antigen, T-Cell, alpha-beta
- Superantigens
- T-Lymphocyte Subsets
- T-Lymphocytes, Cytotoxic
Age-related changes in major lymphocyte subsets were analyzed in 195 cynomolgus monkeys (Macaca fascicularis) aged from one month to 31 years. The percentages of CD20 B cells in peripheral blood lymphocytes (PBL) decreased with age to five years of age, but after that, no significant change was observed. The percentages of CD16 NK cells gradually increased during the first five years and reached the peak at from four to ten years of age, whereas the percentages of CD3 T cells in PBL were relatively constant throughout the life. Among the T cells, the CD4 CD8- T cells decreased, but CD4- CD8 T cells increased within the first decade of life. We further analyzed the expressions of CD28 and CD29 molecules on T cells to determine the relation between age-related activation and phenotypic changes. Almost all CD4 CD8- T cells (> 90%) were CD28 at all ages analyzed, but a clear age-related decrease in CD28 expression was demonstrated in CD4- CD8 T cells during the first ten years. In the case of CD29 expression, age-related increases in CD29hi cells were apparent in both CD4 CD8- and CD4- CD8 T cells during the first ten years. The percentages of CD29hi cells, however, were higher in CD4- CD8 T cells than in CD4 CD8- T cells in all ages analyzed. These results indicated that the age-related changes in percentages of major lymphocyte subsets as well as in phenotypes of T cells might be related to the maturation of the immune system including an increase in memory cells in cynomolgus monkeys.
MeSH Terms
- Aging
- Animals
- Antigens, CD20
- B-Lymphocyte Subsets
- CD28 Antigens
- CD3 Complex
- CD4-CD8 Ratio
- Female
- Integrin beta1
- Killer Cells, Natural
- Lymphocyte Subsets
- Macaca fascicularis
- Male
- Receptors, IgG
- T-Lymphocyte Subsets
Stimulation of the ERK (MAPK) pathway in T-lymphocytes contributes to cell activation and IL-2 production. The ERK pathway is initiated by the activation of the serine/threonine kinase Raf-1 in a Ras-dependent manner. Raf-1 activates the dual-specific kinase MEK, which in turn activates ERK. To see if aging leads to an alteration of Raf-1 kinase activity we performed in vitro kinase assays on Raf-1 isolated from CD4( ) T-cells from young and old mice. We found an age-related impairment in the kinase activity of Raf-1 in T-cells stimulated by a combination of antibodies to the CD3epsilon chain of the T-cell receptor and CD4. Aging led to a two- to fourfold decline in Raf-1 activity (depending on the stimulation time) without a change in the kinetics of enzyme activation. We also found that Raf-1 activation by CD3/CD4 costimulation is lower in memory cells than in naïve cells from mice of the same age. However, aging also leads to a decline in Raf-1 activity in the naïve subset of CD4( ) T-cells, suggesting that two mechanisms lead to the age related decline in Raf-1 function. Finally, we found that antibodies to the costimulatory molecule CD28 trigger Raf-1 activation and enhance anti-CD3-mediated Raf-1 activation but cannot restore Raf-1 activation levels from old T-cells to those seen in young mice. Our data suggest that age-dependent declines in T-cell ERK function are caused by alterations in the signals that activate Raf-1 and that age-dependent defects in T-cell cytokine production and proliferation may be caused at least in part by defects in signals that activate Raf-1.
MeSH Terms
- Aging
- Animals
- CD28 Antigens
- CD3 Complex
- CD4 Antigens
- CD4-Positive T-Lymphocytes
- Cytokines
- Enzyme Activation
- Immunologic Memory
- Lymphocyte Activation
- Male
- Mice
- Mice, Inbred BALB C
- Mice, Inbred C57BL
- Proto-Oncogene Proteins c-raf
- Receptors, Antigen, T-Cell
- T-Lymphocytes
CD4 cells from young (3 months) and old (19 months) mice were stimulated by plate-bound anti-CD3 monoclonal antibody (mAb) alone or also by soluble anti-CD28 mAb. Supernatants were analysed by enzyme-linked immunosorbent assay (ELISA) to determine cytokine concentrations. Total RNA was extracted from cells, reverse transcribed and the cDNA amplified by polymerase chain reaction (PCR) to evaluate the amount of specific mRNA. The results indicate that anti-CD3 alone is not sufficient to induce interleukin-2 (IL-2) production in CD4 cells from both young and old mice. However, anti-CD28, together with anti-CD3 mAb, induces a much higher production of IL-2 in CD4 cells from young as compared with old mice. Conversely, interferon-gamma (IFN-gamma) production is also induced by anti-CD3 alone and is higher in CD4 cells from old as compared with young mice. Upon addition of anti-CD28 mAb, IFN-gamma production increases in both groups, but it remains much higher in old than in young mice. Also the production of IL-4 and IL-10 is induced by anti-CD3 mAb but it is increased by the addition of anti-CD28 mAb. CD4 cells from old mice produce more IL-4 and IL-10 as compared with cells from young mice. The amounts of cytokine specific mRNA in CD4 cells from young and old mice parallel the cytokine levels in culture supernatants. Results on the mRNA turnover indicate that when CD4 cells are stimulated by anti-CD3 or costimulated also by anti-CD28 mAb, the IFN-gamma, IL-4 and IL-10 specific mRNAs are more stable in old than in young mice, suggesting that mRNA stability has a relevant role in the different patterns of cytokine production.
MeSH Terms
- Aging
- Animals
- Antibodies, Monoclonal
- CD28 Antigens
- CD3 Complex
- CD4 Antigens
- Cell Division
- Cells, Cultured
- Cytokines
- Interferon-gamma
- Interleukin-10
- Interleukin-2
- Interleukin-4
- Male
- Mice
- Mice, Inbred C57BL
- Polymerase Chain Reaction
- RNA, Messenger
- T-Lymphocytes
The capacity of neonatal T cells to secrete interleukin-2 (IL-2) has been reported to be variable. We analysed IL-2 production in purified neonatal and adult T cells using polyclonal activator phorbol ester calcium ionophore (PDBu iono) or receptor-mediated anti-CD3/anti-CD3 anti-CD28 stimulation. PDBu iono induced equally high IL-2 levels in both groups and, when stimulated with plate-bound anti-CD3 monoclonal antibody (mAb), the IL-2 secretion by neonatal cells was undetectable and adult cells produced low amounts of IL-2 (mean 331 /- 86 pg/ml). The addition of anti-CD28 mAb to anti-CD3-stimulated cells markedly increased IL-2 production in both cell types, but levels of IL-2 in neonatal T cells remained clearly lower than those of adult T cells (respective mean values: 385 /- 109 pg/ml and 4494 /- 1199 pg/ml). As NF-kappa B is a critical transcription factor in the control of IL-2 expression, we next analysed its nuclear translocation in neonatal and adult T cells using the electrophoretic mobility shift assay and, because induction of reactive oxygen intermediates (ROI) is required for the activation of NF-kappa B, we also analysed levels of intracellular ROI in these cells using the ROI-reactive fluorochrome DCFH-DA and flow cytometry. In neonatal T cells NF-kappa B activation and ROI formation after anti-CD3 stimulation were low compared with adult T cells and, although addition of anti-CD28 mAb increased induction of NF-kappa B and ROI formation, levels similar to those of adults were not achieved. After PDBu iono stimulation, the cells showed similar ROI formation and IL-2 secretion. Our results suggest that reduced IL-2 production by neonatal T cells is specific for anti-CD3 and anti-CD3 anti-CD28-mediated stimulation and that these activators cannot effectively activate the ROI-NF-kappa B signalling pathway in neonatal T cells.
MeSH Terms
- Adult
- Aging
- Antibodies, Monoclonal
- CD28 Antigens
- CD3 Complex
- Cell Culture Techniques
- Fetal Blood
- Humans
- Infant, Newborn
- Interleukin-2
- NF-kappa B
- Reactive Oxygen Species
- T-Lymphocytes
The aging immune system is characterized by a progressive decline in the responsiveness to exogenous antigens and tumors in combination with a paradoxical increase in autoimmunity. From a clinical viewpoint, deficiencies in antibody responses to exogenous antigens, such as vaccines, have a major impact and may reflect intrinsic B cell defects or altered performance of helper T cells. Here we describe that aging is associated with the emergence of an unusual CD4 T cell subset characterized by the loss of CD28 expression. CD28 is the major costimulatory molecule required to complement signaling through the antigen receptor for complete T cell activation. CD4 CD28- T cells are long-lived, typically undergo clonal expansion in vivo, and react to autoantigens in vitro. Despite the deficiency of CD28, these unusual T cells remain functionally active and produce high concentrations of interferon-gamma (IFN-gamma) and interleukin-2 (IL-2). The loss of CD28 expression is correlated with a lack of CD40 ligand expression rendering these CD4 T cells incapable of promoting B cell differentiation and immunoglobulin secretion. Aging-related accumulation of CD4 CD28- T cells should result in an immune compartment skewed towards autoreactive responses and away from the generation of high-affinity B cell responses against exogenous antigens. We propose that the emergence of CD28-deficient CD4 T cells in the elderly can partially explain age-specific aberrations in immune responsiveness.
MeSH Terms
- Aging
- Arthritis, Rheumatoid
- CD28 Antigens
- CD4-Positive T-Lymphocytes
- Cohort Studies
- Cytokines
- Humans
- Immune System
- T-Lymphocytes, Helper-Inducer
Recently, we have found in adult cynomolgus monkeys that substantial peripheral blood CD4 CD8 double-positive (DP) T lymphocytes exhibit a resting memory phenotype and increase in proportion with age. In this study, we investigated whether phenotypic changes occur in the course of the increase in proportion of the DP T cells. The results obtained from 195 clinically healthy monkeys aged from 1 month to 31 years showed that the CD29hi and CD28 subpopulation in the DP T subset increased in proportion with age and that the increase reached a plateau at six years old for the CD29hi subpopulation and at eleven years old for the CD28 one, respectively. The phenotypic alteration preceded the abrupt increase in proportion of the DP T cells and was able to be classified into four phases on the basis of the qualitative and quantitative alteration.
MeSH Terms
- Aging
- Animals
- CD28 Antigens
- CD4-Positive T-Lymphocytes
- CD8-Positive T-Lymphocytes
- Integrin beta1
- Macaca fascicularis
Functional decrements of the immune system have a major contribution to aging and age-related diseases. Here, we further characterize the decline in proportion of CD28-positive T cells previously identified in centenarians. Cohorts of 97 centenarians, 40 subjects aged 70-90 (ELD group), and 40 young adults (under age 40) were phenotyped for T cell surface expression of CD28, CD4, and CD8 antigens. The significant decline in T cells expressing CD28 (p < 10(-4) for comparisons between adults and either ELD or centenarians) affects preferentially the CD8 subset of T cells. This decline accounts largely for the age-related diminution of T cell responsiveness to mitogenic signals. CD28 expression is modulated in T cell cultures in a growth-related fashion and this modulation is dampened in cultures from centenarians. We propose that the decrease in CD28 expression reflects a compensatory adaptation of the immune system during aging in the face of chronic stimulation.
MeSH Terms
- Adult
- Aged
- Aged, 80 and over
- Blood Cells
- CD28 Antigens
- Cell Division
- Cells, Cultured
- Cellular Senescence
- Humans
- Longevity
- T-Lymphocytes
An age-dependent decrease in T cell responsiveness to CD28 costimulation has been described. In order to test the hypothesis that an age-related decrease in CD28 expression by CD8 T lymphocytes might be involved, we analysed 67 healthy donors ranging in age from 15 to 69 years for their CD8 T cell expression of CD28 and CD57. We found a statistically significant decrease of CD28 expression through ageing and a significant increase of CD57 expression, both markers being mutually exclusive. Given that cytomegalovirus (CMV) is reported to induce CD57 expression, and since the carrier status for this ubiquitous virus increases with age in the general population, it seemed essential to evaluate whether the phenotypic age-related changes described in CD8high cells were not influenced by the CMV carrier status of the individuals. Accordingly, we performed a multivariate analysis to assess the independent association of age and CMV carrier status with CD28 and CD57 expression in CD8high cells. Results showed that the progressive decrease in CD8high CD28 CD57- cells was associated only with age, while the expansion of the CD8high CD28- CD57 subset depended both on age and CMV, although mainly on age. We conclude that ageing is accompanied by a progressive loss of CD28 expression in CD8 T cells and a reciprocal enhancement of CD57 expression, both facts being probably related to the repeated antigenic stimulation occurring throughout life.
MeSH Terms
- Adolescent
- Adult
- Aged
- Aging
- CD28 Antigens
- CD57 Antigens
- CD8 Antigens
- Humans
- Immunophenotyping
- Middle Aged
- T-Lymphocyte Subsets
Components and functions of the immune system change during postnatal development, not only in the first years of life, but well through adolescence and even into adult life. These age-dependent changes within the immune system greatly complicate any attempt to assess pathological alterations of immunologic variables in children. The need for studies on possible substance-induced changes, including risk assessment of environmental chemicals, has increased the necessity to establish reference ranges for certain immunologic variables against which an abnormal developmental status can be evaluated. In the present study age-related changes of surface receptors on peripheral white blood cells were studied in 82 children, aged between 2 months and 17 years. The blood samples were triple labeled with monoclonal antibodies followed by a whole blood lysis technique and were subsequently analyzed by flow cytometry. Complex statistical analyses were performed in order to determine probability ranges for some immunological variables. In this paper we describe the age-dependent development of components involved in major maturational processes, including the appearance and varying expression of adhesion receptors (CD11a, CD18, CD28, CD29, CD44, CD49d and CD54) on CD4 "helper" cells and CD8 "suppressor and cytotoxic" cells. A clear-cut increase of high epitope density expression of the integrins on both CD4 and CD8 cells was noted. These results suggest that the components of immune T cells for performing adhesion by interacting with other cells and many matrix components are largely acquired during postnatal development. Maximal levels of adhesion receptor expression are reached at different ages depending on the specific T cell subpopulation.
MeSH Terms
- Adolescent
- Adult
- Aged
- Aging
- Child
- Child, Preschool
- Evaluation Studies as Topic
- Female
- Humans
- Infant
- Integrins
- Killer Cells, Natural
- Lymphocytes
- Male
- Middle Aged
- Receptors, Cell Surface
- Reference Values
- T-Lymphocytes
Changes in T cell populations and concomitant perturbation of T cell effector functions have been postulated to account for many aging-related immune dysfunctions. Here, we report that high frequencies of CD28(null) CD4 T cells were found in elderly individuals. Because deviations in the function of these unusual CD4 T cells might be directly related to CD28 deficiency, we examined the molecular basis for the loss of CD28 expression in CD4 T cells. In reporter gene bioassays, the minimal promoter of the CD28 gene was mapped to the proximal 400 base pairs (bp) of the 5' untranslated region. CD28 deficiency was associated with the loss of two noncompeting binding activities within a 67-bp segment of the minimal promoter. These binding activities were not competed by consensus Ets, Elk, or AP3 motifs that were found within the sequence stretch. The DNA-protein complexes were also not recognized by antibodies to Ets-related transcription factors. Furthermore, introduction of mutations into the 67-bp segment at positions corresponding to the two DNA-protein interaction sites, i.e. nucleotides spanning -206 to -179 and -171 to -148, resulted in the loss of specific nuclear factor binding activities and the abrogation of promoter activity. These observations implicate at least two regulatory motifs in the constitutive expression of CD28. The loss of binding activity of trans-acting factors specific for these sequences may contribute to the accumulation CD4 CD28(null) T cells during aging.
MeSH Terms
- Aging
- Base Sequence
- Binding Sites
- CD28 Antigens
- CD4-Positive T-Lymphocytes
- Gene Expression Regulation
- Humans
- Molecular Sequence Data
- Nuclear Proteins
- Sequence Deletion
Transplantation of T-cell depleted bone marrow has been associated with an increased risk of graft failure, requiring additional immunosuppression to prevent this complication. To determine the effect of graft rejection prophylaxis with posttransplant anti-thymocyte globulin and methylprednisolone on immune reconstitution, the lymphoid phenotype, function, and infectious complications of 170 recipients of a T-cell depleted bone marrow transplantation, 57 of whom received prophylaxis, were analyzed. Neutrophil recovery and normalization of T-cell numbers were more rapid in patients given anti-thymocyte globulin and methylprednisolone. Adults given graft rejection prophylaxis had prolonged inversion of their CD4/CD8 ratio, increased numbers of CD8 CD11b , HLA-DR , CD57 , CD28- T cells, and delayed recovery of T-cell mitogen responses when compared to adults not given ATG and steroids. Even without posttransplant immunosuppression to prevent graft failure, adults experienced delayed recovery of total and CD45RA CD4 cells, prolonged inversion of the CD4/CD8 ratio, and delayed recovery of T-cell mitogen responses when compared to children. During the first posttransplant year, Epstein-Barr Virus-Associated Lymphoproliferative disorders and opportunistic infections were increased in patients given prophylaxis. Patients who developed an opportunistic infection or EBV-LPD had significantly fewer circulating CD4 T cells than those who did not. This study demonstrates that older age and graft rejection prophylaxis, rather than T-cell depletion alone, are associated with delayed immune reconstitution. In addition, it suggests that CD4 cell counts may be useful in predicting which patients are at increased risk of developing opportunistic infections following successful engraftment.
MeSH Terms
- Adolescent
- Adult
- Aging
- Bone Marrow Transplantation
- Case-Control Studies
- Child
- Child, Preschool
- Female
- Graft Rejection
- Humans
- Infant
- Lymphocyte Count
- Lymphocyte Depletion
- Male
- Middle Aged
- Risk Factors
- T-Lymphocytes
It is generally assumed that T cell proliferation is impaired in aged individuals. We report data on the proliferative capability of peripheral blood mononuclear cells (PBMC) and T lymphocytes from 40 healthy people of different ages, (19-107 years), including 14 centenarians, to defined mitogenic stimuli. We observed no age-related proliferative impairment both in PBMC and in purified T cells stimulated by anti-CD3 mAb or phorbol myristate acetate (PMA). Furthermore, T cells stimulated by anti-CD3 mAb or PMA and costimulated by CD28 mAb did not proliferate differently among young, middle aged subjects and centenarians. Thus, short term T cell proliferation is not affected even at extreme age when well defined stimuli are used on cells deriving from carefully selected healthy subjects.
MeSH Terms
- Adult
- Aged
- Aged, 80 and over
- Aging
- CD28 Antigens
- Cell Division
- Cell Separation
- Female
- Humans
- Leukocytes, Mononuclear
- Male
- Middle Aged
- Mitogens
- Reference Values
- T-Lymphocytes
To understand mechanism underlying the age-related impairment of T cell functions, changes in the expression of cell surface receptors were examined in T cells after mitogenic stimulation by flow cytometry and results were compared between young and old mice. Before stimulation, no significant difference was observed in the density of TCR alpha beta, CD3, CD122 (IL-2R beta), IL-2R gamma, CD28 and CD95 (Fas) of T cells between young and old mice. As for CD25(IL-2R alpha) and CTLA-4, relative intensity and percentage of positive cells were higher in old than in young mice, although the levels were low compared with those after stimulation. After mitogenic stimulation, increased expression of the density was observed in CD25, IL-2R beta, IL-2R gamma, CD28, CTLA-4 and CD95 and the magnitude of increase was more pronounced in T cells from young than those from old mice. The expression of TCR alpha beta and CD3 decreased after mitogenic stimulation, and the degree of expression quickly recovered to the initial level in young mice, but not in old mice. Lower expression of TCR, IL-2 receptors and co-stimulatory molecules in T cells from old mice could be responsible for the impaired proliferation after mitogenic stimulation.
MeSH Terms
- Abatacept
- Aging
- Animals
- Antigens, CD
- Antigens, Differentiation
- CD28 Antigens
- CD3 Complex
- CTLA-4 Antigen
- Cell Division
- Concanavalin A
- Flow Cytometry
- Immunoconjugates
- Mice
- Mice, Inbred C57BL
- Mitogens
- Receptors, Antigen, T-Cell
- Receptors, Antigen, T-Cell, alpha-beta
- Receptors, Interleukin-2
- Spleen
- T-Lymphocytes
- fas Receptor
Peripheral blood mononuclear cells (PBMC) of frail elderly nursing home residents had significantly higher PHA-induced interleukin-10 (IL-10) production compared to PBMC's from young control subjects. No correlation was observed between IL-10 production and interleukin-12 (IL-12) p40 production, proliferative response or with the proportion of CD28-negative T cells. To better characterize the host response to a ubiquitous pathogen, the dose response and time-dependent (kinetic) production of IL-10 and IL-12 p40 of PBMC stimulated with Staphylococcus aureus Cowan (SAC) was studied. IL-10 production continued to increase at 48 h, while IL-12 p40 levels declined or remained stable, in both young and elderly subjects. In analyzing how excessive IL-10 production might influence antigen presenting cell functions, IL-12 was markedly inhibited by recombinant IL-10 (rIL-10), while anti-IL-10 enhances IL-12 p40 production in cultures from young controls; but the PBMC cultured from an elderly cohort were not able to generate similar absolute levels of IL-12 p40 even in the presence of anti-IL-10. These preliminary data suggest that there may be both over production of IL-10 in some individuals, as well an an impaired ability to upregulate a T Helper 1 (type 1) reaction. These age-related changes could even be more dramatic at the tissue level and contribute to the impaired delayed type hypersensitivity (DTH) and failed host defense to infection, such as to primary and reactivation tuberculosis.
MeSH Terms
- Aged
- Aged, 80 and over
- Aging
- Animals
- Cells, Cultured
- Frail Elderly
- Humans
- Interleukin-10
- Interleukin-12
- Leukocytes, Mononuclear
- Nursing Homes
- Phytohemagglutinins
- Rats
- Recombinant Proteins
- Staphylococcus aureus
- Th1 Cells
- Th2 Cells
The author has focused the subject on the perduration of puberty thymus involution as a cause of immunity aging, a term in which he does not include senescence. The decrease between immune reactions against HIV1 at 25 years of age and those at 35 is considerable; the decrease is also indirectly revealed by spontaneous tumor exponentially growing incidence after 40 years in man and its equivalent, 16 months in mice: the immunity parameters indicate a regression correlated with this incidence growth. He regrets the neglect of suppressor cell and anti-idiotype problems by the basic immunologic research. Given the role of cofactors non specifically related to the antigen, such as that CD28 and its ligands, he suggests the interest to approach immunology via the science of chaos and fractals, which would be more appropriate than classical methodology to study highly complex phenomena on which apparently minimal interventions may induce considerable effects.
MeSH Terms
- Adult
- Aged
- Aging
- Animals
- Cellular Senescence
- Humans
- Immunity
- Lymphocytes
- Mice
- Middle Aged
- Puberty
- Thymus Gland
Highly purified CD4 CD45RA cells from cord blood and peripheral blood from healthy adults were studied. The levels of expression of the CD2, CD3, CD4 and CD28 antigens were similar; however, CD45 and CD45RA antigen expression were slightly lower in cord cells. The reduced expression of the CD45RA antigen on cord CD4 T cells was confirmed in whole blood. Functional assessment revealed deficiencies in cord CD4 CD45RA T cells. Interleukin-2 (IL-2) production in response to specific triggering via CD2 monoclonal antibody (mAb) alone, or CD2 mAb in combination with CD28 mAb showed marked underproduction (about 10% of adult production). When CD25 expression was examined, it was observed that the proportion of activated CD4 CD45RA T cells in cord blood was lower than in adult (about 20% of adult expression). Proliferation to CD2 mAbs or CD2 28 mAbs of cord blood native cells was similarly depressed. Investigation of IL-2 mRNA expression under these stimulatory conditions paralleled the results observed for CD25 expression, IL-2 production and proliferation. When phorbol 12-myristate 13-acetate (PMA) was added to the cells triggered with CD2 28mAbs, the responses examined were enhanced in both cord and adult blood with no significant differences between the groups. These findings suggest that under identical conditions of stimulation, purified cord blood CD4 CD45RA T cells do not acquire similar activation status as their adult counterparts. These findings may help in understanding the reduced graft-versus-host disease (GVHD) observed in cord blood stem cell transplantation.
MeSH Terms
- Adult
- Aging
- CD4-Positive T-Lymphocytes
- Cell Culture Techniques
- Cell Division
- Cell Separation
- Fetal Blood
- Flow Cytometry
- Humans
- Infant, Newborn
- Interleukin-2
- Leukocyte Common Antigens
- Lymphocyte Activation
- RNA, Messenger
The biological basis for reduced Ig production by naive newborn B cells compared to adult peripheral blood B cells is not fully understood. In a Con A IL-2 T cell-dependent system using "competent" adult T cells, adult B cells produced large amounts of IgM, IgG, and IgA, while cord B cells were restricted to low levels of only IgM production. Cord B cell activation was also diminished. The contribution of specific B-T cell contact-mediated events to the diminished cord B cell response in this system, using mAbs to CD40, CD28, CD80, and CD72, were investigated, as well as regulation of B cell Ig production by cytokines. alphaCD72 ligation increased cord B cell activation and IgM production, but did not affect adult B cells. Blocking alphaCD40 mAb inhibited cord B cell Ig production completely, but only partly inhibited adult B cell Ig production even at high concentration, suggesting a greater sensitivity of cord B cells to disruption of the CD40-CD40L interaction. Addition of IL-10 did not increase cord B cell Ig production, while adult B cell Ig production was increased. However, combined addition of IL-10 and alphaCD72 significantly increased cord B cell Ig production over that in the presence of either alphaCD72 or IL-10 alone, but had no effect on adult B cells over that of IL-10 alone. These data suggest that the diminished T cell-dependent response of cord B cells is due to reduced or absent CD72 ligation. CD72 ligation plays an important role in the induction of primary responses by naive B cells. CD72 modulation of naive B cell sensitivity to IL-10 stimulation may have implications in the induction of class switch, which is deficient in newborn B cells. Since all T cells express CD5 constitutively, these data also suggest the existence of another ligand for CD72.
MeSH Terms
- Adult
- Aging
- Antibodies, Monoclonal
- Antibody Formation
- Antigens, CD
- Antigens, Differentiation, B-Lymphocyte
- B-Lymphocytes
- Cell Differentiation
- Cells, Cultured
- Concanavalin A
- Cytokines
- Fetal Blood
- Histocompatibility Antigens Class II
- Humans
- Interleukin-10
- Interleukin-2
- Lymphocyte Activation
- Lymphocyte Cooperation
- Middle Aged
- T-Lymphocytes
Ageing is associated with complex remodelling in the phenotypic and functional profiles of T lymphocytes. We investigated whether expression of CD28 antigen on T cells is conserved throughout adulthood and ageing in humans. For this purpose we analysed T cells obtained from peripheral blood of 102 healthy people of ages ranging from 20 to 105 years. We found an age-related increase of CD28- T cells in percentage and absolute number, predominantly among CD8 T cells. CD28- T cells from aged donors analysed by flow cytometry appeared as resting cells (not expressing CD25, CD38, CD69, CD71, DR), bearing markers of cytotoxic activity (CD 11b and CD 57) and with a phenotype compatible with 'memory' cells (up-regulated CD2 and CD11a; CD62L absent). At the functional level, freshly isolated purified CD28- CD8 T cells showed high anti-CD3 redirected cytotoxic activity against Fc-bearing P815 cells. The same activity tested on freshly isolated bulk T lymphocytes was significantly augmented with age. We found a positive correlation between age, number of CD8 CD28- T cells and anti-CD3 redirected cytotoxicity by freshly isolated T cells. These data suggest that an activation of unknown nature within the cytotoxic arm of the immune system occurs with age. We speculate that these cytotoxic T lymphocytes (CTL) in vivo may constitute armed effector cells for immediate killing of targets bearing peptides from pathogens of intracellular origin.
MeSH Terms
- Adult
- Aged
- Aged, 80 and over
- Aging
- CD28 Antigens
- CD3 Complex
- CD8-Positive T-Lymphocytes
- Cell Separation
- Cytotoxicity, Immunologic
- Flow Cytometry
- Humans
- Lymphocyte Count
- Middle Aged
Oligoclonality of the CD8 T cell subset is a common and characteristic feature of the normal human peripheral T cell repertoire. These clonally expanded populations are predominantly found in a CD57 or CD28- CD8 T cell subset. While CD8 oligoclonality is somewhat more common in the older age group, it is also very prevalent in young to middle-aged adults. Recent experiments have also demonstrated that the clonally expanded populations may actually occur in two distinct subpopulations of CD8 CD28- cells, distinguished by the expression of the CD57 surface marker. A major difficulty with studies involving CD8 CD28- CD57 T cells is their relative lack of proliferative capacity. We have recently investigated the possibility that this phenotype may be due to a state of "replicative senescence" in some cases. In this regard, we have demonstrated that the telomere lengths of CD8 CD28- T cells are generally shorter than that of their CD8 CD28 counterparts, consistent with a distinct replicative history for the CD8 CD28- population. Additional studies of the normal biology of clonally expanded CD8 T cells are likely to yield important insights into immune function in health and disease.
MeSH Terms
- Aging
- CD8-Positive T-Lymphocytes
- Clone Cells
- Humans
- Infections
- Receptors, Antigen, T-Cell
We previously reported that T cell proliferation in response to a primary signal through the T cell receptor (TCR) and a costimulatory signal via the CD28 molecule is impaired in healthy, aged mice. Here we extend these studies to examine factors which may be involved in this defect in T cells from aged mice. To determine if age-related changes in cytokine production might be responsible, splenic T cells from young (2-4 months) and aged (20-26 months) mice were stimulated with immobilized anti-CD3 epsilon and soluble anti-CD28 mAbs in the presence of exogenous IL-2, IL-4, IFN-gamma, IL-1 alpha, or IL-6. No improvement in the proliferative response of T cells from aged mice was found following the addition of any cytokine. In addition, the decreased proliferative response of T cells from aged mice was not caused by the enhanced production of IFN-gamma or other inhibitory factors. Interestingly, despite the age-related reduction in proliferation, no significant difference was found in the percentage of live cells entering the S, G2, or AM phase of the cell cycle in stimulated T cells from young and aged mice. Instead, anti-CD28-mediated costimulation was found to rescue T cells from young mice from anti-CD3epsilon-induced cell death, but did not rescue T cells from aged mice. This failure of T cells from aged mice to respond to costimulatory signals appears to contribute to the decreased proliferation observed from cultures containing these cells, and may be involved in many other age-related alterations in immunological responsiveness.
MeSH Terms
- Aging
- Animals
- CD28 Antigens
- Cell Death
- Growth Inhibitors
- Interleukin-2
- Interleukin-4
- Lymphocyte Activation
- Lymphocyte Count
- Male
- Mice
- Mice, Inbred C57BL
- Mice, Inbred CBA
- T-Lymphocytes
We previously have shown that T cell proliferation in response to a primary signal through the CD3 epsilon chain and a costimulatory signal via the CD28 molecule is impaired in healthy, aged mice. To determine whether age-related alterations in cytokine production might explain the reduced proliferative responses of T cells from aged mice, we examined the secretion of the major T cell immunoregulatory cytokines, IFN-gamma, IL-4, and IL-2. Splenic T cells from young (2 to 4 mo) and aged (20 to 26 mo) mice were studied. T cells were stimulated with immobilized anti-CD3 epsilon chain mAb and soluble anti-CD28 mAb for 24 h. T cells from aged mice, when compared with young controls, showed increased IFN-gamma production, no difference in IL-4 production, and decreased IL-2 production. Most IFN-gamma was produced by CD8 T cells, whereas most IL-2 and IL-4 was produced by CD4 T cells. Both CD4 and CD8 T cells from aged mice produced significantly more IFN-gamma than corresponding cells from young mice. This increased production could be accounted for by increased numbers of CD4 CD44high and CD8 CD44high T cells in aged animals. CD4 CD44high and CD8 CD44high T cells from young mice produced comparable amounts of IFN-gamma as corresponding cells from aged mice. In contrast to unseparated splenic T cells, no age-related difference in IL-2 or IL-4 production by purified CD4 T cells was observed. Similarly, when CD4 T cells were further separated into CD44low and CD44high subpopulations, no age-related difference in IL-2 production was found. Therefore, we found no consistent evidence that diminished production of the major T cell growth factors, IL-2 and IL-4, is responsible for the age-related decrease in the proliferation of T cell subpopulations that were stimulated in vitro through the CD3 epsilon chain and costimulated via the CD28 molecule. The physiologic relevance of increased IFN-gamma production by T cells from aged mice is unknown.
MeSH Terms
- Aging
- Animals
- CD4-Positive T-Lymphocytes
- CD8-Positive T-Lymphocytes
- Cytokines
- Hyaluronan Receptors
- Immunophenotyping
- Interleukin-2
- Interleukin-4
- Male
- Mice
- Mice, Inbred C57BL
- Mice, Inbred CBA
- Spleen
- T-Lymphocyte Subsets
Human monoclonal T lymphocyte populations maintained in long-term culture by intermittent reactivation via the antigen receptor and supplied with exogenous interleukin 2 manifest finite proliferative lifespans. T lymphocytes cloned from mature peripheral T cells of adult donors were constantly lost from the time point of their first isolation up to an estimated maximum of 80 population doublings (PD) for the longest lived. T lymphocytes cloned from T cell progenitors in bone marrow, on the other hand, survived for a maximum of ca. 100 PD. One facet of the functional capacity of cells derived from these two different sources was assessed by measuring their autocrine proliferation after mitogenic stimulation. For a majority of T cell clones (TCC), autocrine proliferative capacity decreased as a function of culture age, becoming absent by 50 PD for adult-derived-TCC and by 70 PD for bone marrow-derived TCC, thereby clearly occurring prior to the end of the proliferative life spans of the clones. Limiting dilution frequency analysis showed that the number of autocrine proliferative precursors within these monoclonal populations declined with age, paralleling loss of autocrine proliferative capacity in the 'bulk' clones. Of a variety of surface structures monitored during culture ageing of TCC, the density of expression of the coreceptor molecule CD28 was found to correlate with decreasing autocrine proliferative capacity in two-thirds of the clones. Thus, at least for a fraction of monoclonal human T lymphocytes, decreasing autocrine proliferative capacity, a measure of clonal expansion, may correlate with decreasing numbers of CD28 molecules expressed on the surface and therefore presumably with the strength of costimulatory signal delivered via this important coreceptor.
MeSH Terms
- Adult
- Aging
- Cell Division
- Cells, Cultured
- Clone Cells
- Cytokines
- Humans
- Phenotype
- T-Lymphocytes
It is well documented that the proliferative capacity of T cells declines with advancing age. There are, however, conflicting data as to the role of the accessory cell and whether or not this loss in responsiveness extends to all T-cell stimuli and to all T cells. We report here on the capacity of subpopulations of peripheral blood CD4 T cells from the healthy aged to proliferate in response to anti-CD2 receptor-induced activation in the complete absence of accessory cells by using various exogenous cofactors as second signals. These costimulatory factors included phorbol 12-myristate 13-acetate (PMA), interleukin (IL)-1, IL-2, IL-6 and IL-7 and the monoclonal antibodies, anti-CD28 and anti-CD44. Under these conditions, the proliferative responsiveness of CD4 CD45RO T cells from the aged was found to be comparable to young control cells for all stimuli tested, except anti-CD2 plus IL-7. This suggests that signal transduction pathways involving CD2, except IL-7-mediated events, are essentially intact in 'old' memory CD4 T cells. On the other hand, several cofactors, namely IL-2, IL-6, IL-7 and to a lesser extent IL-1 beta and PMA, failed to support adequately CD2-induced activation in 'old' CD4 CD45RA T cells suggesting severe and multiple signalling deficiencies in this subset.
MeSH Terms
- Aged
- Aged, 80 and over
- Aging
- CD2 Antigens
- Cell Culture Techniques
- Cell Division
- Female
- Humans
- Interleukins
- Leukocyte Common Antigens
- Lymphocyte Activation
- Male
- T-Lymphocyte Subsets
Protein-tyrosine kinases have been implicated in signal transduction in T lymphocytes after stimulation of many cell-surface molecules, including the T-cell antigen receptor, CD4, CD8, CD2, CD5, and CD28. Yet the identities of many of these tyrosine kinases remain unknown. We have isolated a murine tyrosine kinase gene, called Tsk for T-cell-specific kinase, that appears to be exclusively expressed in T lymphocytes. The Tsk cDNA clone encodes a polypeptide of 70 kDa, which is similar in sequence to both the src and abl families of tyrosine kinases. Sequence comparisons also indicate that Tsk contains one src-homology region 2 domain and one src-homology 3 domain but lacks the negative regulatory tyrosine (src Tyr-527) common to src-family kinases. In addition, Tsk expression is developmentally regulated. Steady-state Tsk mRNA levels are 5- to 10-fold higher in thymocytes than in peripheral T cells and increase in the thymus during mouse development from neonate to adult. Furthermore, Tsk is expressed in day 14 fetal thymus, suggesting a role for Tsk in early T-lymphocyte differentiation.
MeSH Terms
- Aging
- Amino Acid Sequence
- Animals
- Animals, Newborn
- Base Sequence
- Cell Differentiation
- Cloning, Molecular
- Gene Expression Regulation
- Genes, abl
- Genes, src
- Mice
- Molecular Sequence Data
- Molecular Weight
- Polymerase Chain Reaction
- Protein-Tyrosine Kinases
- Signal Transduction
- T-Lymphocytes
- Thymus Gland
- Tissue Distribution
To determine whether T cells, like B cells, can become clonally expanded in normal individuals as a function of age, we compared the T cell V beta repertoire of cord blood to that of peripheral blood from normal donors over 65 yr of age. T cells from elderly subjects contained expanded subsets (greater than the mean three standard deviations) of T cell receptor (TCR) V beta populations. These expanded subsets were observed primarily among CD8, but not CD4 cells, represented up to 37.5% of all CD8 cells, and were present in most elderly subjects. An expanded V beta 5.2/3 CD8 subset and a V beta 6.7a CD8 subset from separate donors were analyzed by reverse transcriptase-polymerase chain reaction, cloning and sequencing of the TCR beta chain VDJ junction. In both cases the expanded subsets were mono- or oligoclonal while control CD4 populations were polyclonal. Using two-color flow cytometry it was possible to identify the expanded V beta 6.7a subset as CD8 CD28-CD11b cells. In three of five random old subjects similar expansions of V beta subsets were found specifically in the CD8 CD28- subpopulation, an interesting subset of cytotoxic T lymphocytes, known to lack proliferative responses to TCR stimuli. It is common practice to use the demonstration of clonality as a diagnostic indicator for T cell lymphoma/leukemia. In view of the high frequency of expanded T clones of T cells in normal elderly subjects the diagnostic usefulness of this test should be reexamined.
MeSH Terms
- Aged
- Aging
- Amino Acid Sequence
- Base Sequence
- Clone Cells
- DNA
- Fluorescent Antibody Technique
- Humans
- Molecular Sequence Data
- Monoclonal Gammopathy of Undetermined Significance
- Polymerase Chain Reaction
- Receptors, Antigen, T-Cell
- T-Lymphocyte Subsets
The influence of ageing on phenotype and function of CD4 T cells was studied by comparing young (19-28 years of age) and aged (75-84 years of age) donors that were selected using the SENIEUR protocol to exclude underlying disease. An age-related increase was observed in the relative number of memory cells, not only on the basis of a decreased CD45RA and increased CD45RO expression, but also on the basis of a decrease in the fraction of CD27 CD4 T cells. Our observation that the absolute number of CD45RO CD4 T cells was increased, while absolute numbers of CD27-CD4 T cells remained unchanged in aged donors, indicates that the latter subset does not merely reflect the size of the CD45RO CD4 T cell pool. The increased fraction of memory cells in the aged was functionally reflected in an increased IL-4 production and T cell proliferation, when cells were activated with the combination of anti-CD2 and anti-CD28, whereas IL-2 production was comparable between both groups. No differences were observed with respect to proliferative T cell responses or IL-2 production using plate-bound anti-CD3 or phytohaemagglutinin (PHA). The observation that IL-4 production correlated with the fraction of memory cells in young donors but not in aged donors suggests different functional characteristics of this subset in aged donors.
MeSH Terms
- Adult
- Aged
- Aged, 80 and over
- Aging
- CD4-Positive T-Lymphocytes
- Cell Differentiation
- Humans
- Immunologic Memory
- Interleukin-2
- Interleukin-4
- Leukocyte Common Antigens
- Lymphocyte Activation
- Phenotype
- T-Lymphocyte Subsets
- Tumor Necrosis Factor Receptor Superfamily, Member 7
Glucocorticoids (GC) are known to inhibit the proliferative response of leukocytes after mitogenic activation. Until now, the effects of GC on the immune system have been studied predominantly in adults. However, GC are frequently administered to human fetuses and newborns for the prevention and treatment of respiratory distress syndrome. The immune system of human newborns is still a functionally immature system. Therefore, we wondered whether the immaturity is also reflected by altered responses to hormonal signals such as glucocorticoids. We studied the effects of the GC dexamethasone (DEX) on the proliferation of peripheral blood mononuclear cells and T cells in vitro after stimulation with phytohemagglutinin, anti-CD3, anti-CD3/anti-CD28 or anti-CD2/anti-CD28. Our data demonstrate that neonatal cells are much more sensitive to inhibition of the proliferative response by DEX than adult cells (ED50 1 /- 0.8 nM vs. 221 /- 135 nM). This difference in sensitivity is not related to differences in affinity and capacity of binding of [3H] DEX. Moreover, we show that the mechanisms of GC inhibition differ between adult and neonatal cells. In adult cells, addition of interleukin (IL)-2 does not restore DEX inhibition of the proliferative response. In contrast, the proliferative response of neonatal cells can be restored completely by the addition of IL-2. These data suggest that the primary target of GC in neonatal cells is inhibition of IL-2 production. In adult cells, other mechanisms are responsible for inhibition of T cell proliferation.
MeSH Terms
- Adult
- Aging
- Antibodies, Monoclonal
- CD28 Antigens
- Cell Division
- Cells, Cultured
- Dexamethasone
- Fetal Blood
- Gene Expression Regulation
- Humans
- Immunosuppressive Agents
- Infant, Newborn
- Interleukin-2
- Leukocyte Common Antigens
- Leukocytes, Mononuclear
- Lymphocyte Activation
- Muromonab-CD3
- Phytohemagglutinins
- Receptors, Interleukin-2
- T-Lymphocytes
The mammalian immune system is multicellular in composition, and its proper function requires careful control over complex developmental pathways and many distinct types of effector responses. Numerous overlapping mechanisms of intercellular communication are needed to accomplish the tasks of proper regulation of the diverse cell types that constitute this essential protective system. One mechanism occurs by direct cell-to-cell contact through the interaction of membrane-associated molecules. Examples of this type of communication include the interaction that takes place between the antigen-specific T-cell receptor and the foreign peptides that are bound to major histocompatibility complex molecules, as well as costimulatory molecule interactions with their specific ligands expressed on antigen-presenting cells (e.g., CD28 and B7-1 or B7-2). A second mechanism occurs through the production, secretion, and activities of soluble mediators, collectively known as the cytokines. The cytokines are represented by a large and diverse group of molecules that are produced by a wide variety of cell types. Unique species of cytokines bind to specific membrane-associated receptors on target cells, inducing the activation of particular signal-transduction pathways. These processes subsequently lead to the diversity of cytokine-linked changes in cellular physiology. Some of the cytokines exert their influences in vivo via endocrine routes, although it is far more common for intercellular communication via cytokines to occur microenvironmentally via paracrine or autocrine pathways. The object of this review is to provide evidence supporting the concept that one mechanism for upstream regulation of cytokine production by immunocompetent cell types is controlled by the regulatory activities of various steroid hormones. Strain variation in susceptibility to infectious agents, the condition of immunosenescence, and the processes that control the development of common mucosal immunity are used as examples of immune mechanisms that may be under steroid hormone control.
MeSH Terms
- Aging
- Animals
- Antibody Formation
- Disease Susceptibility
- Endocrine Glands
- Glucocorticoids
- Hormones
- Humans
- Immune System
- Infections
- Mucous Membrane
- Species Specificity
CD4 T cells from young and aged mice were sorted into Mel-14 cells which are regarded as naive cells and Mel-14- cells which are regarded as memory cells. These subsets were stimulated in short-time cultures with anti-CD3 or anti-CD3/anti-CD28 in order to determine the presence of Th1 and/or Th2 cytokines. Based on the simultaneous production of IL-2, IL-4, IL-10, and IFN-gamma upon anti-CD3 stimulation by Mel-14- cells from young and aged mice, it is concluded that this cell population comprises Th1, Th2, and/or Th0 cells. Mel-14 cells from young mice only secrete substantial amounts of IL-2 in the presence of anti-CD28 as a costimulatory signal and can therefore be regarded as Th precursor cells. By contrast, Mel-14 cells from aged mice responded to anti-CD3 alone, not only by the production of IL-2 but also by the production of high amounts of IFN-gamma and minute amounts of IL-4 and IL-10, suggesting that these "naive" cells in aged mice are enriched for Th1 cells. This was not due to lack of CD28 triggering since anti-CD28 enhanced IFN-gamma as well as IL-4 and IL-10 to a similar extent. Our data therefore indicate that Mel-14 is not exclusively expressed on naive CD4 T cells.
MeSH Terms
- Aging
- Animals
- CD28 Antigens
- CD4-Positive T-Lymphocytes
- Cell Adhesion Molecules
- Cell Separation
- Flow Cytometry
- Immunologic Memory
- L-Selectin
- Mice
- Mice, Inbred CBA
- T-Lymphocyte Subsets
- Th1 Cells
- Th2 Cells
The ability of T cells to proliferate in response to a number of stimuli is impaired in healthy, aged individuals. T cells from young (2 to 4 mo) and aged (20 to 26 mo) mice were stimulated with immobilized anti-CD3 epsilon-chain mAb and soluble anti-CD28 mAb. T cells from young and aged mice proliferated comparably in response to anti-CD3 epsilon mAb alone. However, aged T cells were significantly less responsive to costimulation by anti-CD28 mAb. This decreased response of aged T cells was seen at all dosages tested of anti-CD3 epsilon and anti-CD28 mAbs and in the presence and absence of APC. Similar results were observed when costimulation was provided by B7-transfected L cell fibroblasts. T cells from young and aged mice had comparable expression of CD28 by flow cytometry, both before and after stimulation. The defect in response to CD28 was seen both in CD4 and CD8 T cells and in CD44lo (naive) and CD44hi (memory) T cells. The impaired response to costimulation mediated by CD28 on T cells from aged mice may be an important factor in reduced T cell responses associated with aging.
MeSH Terms
- Aging
- Animals
- CD28 Antigens
- CD3 Complex
- CD4-Positive T-Lymphocytes
- CD8 Antigens
- Carrier Proteins
- Hyaluronan Receptors
- Lymphocyte Activation
- Male
- Mice
- Mice, Inbred C57BL
- Mice, Inbred CBA
- Mice, Inbred DBA
- Receptors, Cell Surface
- Receptors, Lymphocyte Homing
- T-Lymphocyte Subsets
Aging is accompanied by an increased fraction of memory CD4 T cells. Despite the fact that human memory cells have been reported to produce high levels of IL-2, studies in mice and man indicate an age-related decline in IL-2 production. In the present study, we examined whether these conflicting results depend on the activation pathway employed in a comparison of phenotypically distinct CD4 T cells from young and aged mice. Our data indicate an age-related decline in IL-2 production by CD4 T cells when the cells were stimulated with concanavalin A in the presence of accessory cells or the combination of immobilized anti-CD3 and soluble anti-CD28. However, when CD4 T cells were only stimulated with immobilized anti-CD3, an age-related increase in IL-2 production was observed. This age-related increase in IL-2 could be attributed to the ability of CD4 T cells from aged mice to produce IL-4 on this stimulation, since anti-IL-4 inhibited the IL-2 production in these cultures to levels found with cells from young mice. The addition of exogenous IL-4 greatly enhanced the IL-2 production of CD4 T cells from young mice to levels far beyond that of the aged counterparts, emphasizing the dominant role of IL-4 in the induction of IL-2 stimulated with immobilized anti-CD3. No differences were observed in the activation requirements of Mel14- CD4 T cells from young and aged mice.(ABSTRACT TRUNCATED AT 250 WORDS)
MeSH Terms
- Aging
- Animals
- CD3 Complex
- CD4-Positive T-Lymphocytes
- Carrier Proteins
- Cell Adhesion Molecules
- Cells, Cultured
- Hyaluronan Receptors
- Immunologic Memory
- Intercellular Adhesion Molecule-1
- Interleukin-2
- Interleukin-4
- L-Selectin
- Lymphocyte Activation
- Male
- Mice
- Mice, Inbred CBA
- Receptors, Cell Surface
- Receptors, Lymphocyte Homing
We have produced a hamster mAb, H1.2F3, which was derived by immunization with a murine TCR-gamma delta epidermal T cell line. H1.2F3 immunoprecipitates a cell surface-expressed disulfide-linked dimer that has a m.w. of 85,000 under non-reducing conditions and consists of subunits of 35,000 to 39,000 m.w. This dimer is distinct from the CD3-associated TCR-gamma delta complex (CD3/TCR), inasmuch as H1.2F3 does not co-precipitate or co-modulate with the CD3/TCR complex and recognizes an Ag with a single-peptide backbone of 22,000 m.w. after N-Glycanase treatment. H1.2F3 is weakly reactive with a small percentage of cells from unfractionated thymus, spleen, or lymph node, but reactivity with both T and B lymphocytes is markedly enhanced by a brief period of stimulation with Con A or PMA in vitro. This enhancement requires de novo protein synthesis. Enhanced expression of the H1.2F3 Ag can also be induced in vivo by injection of Con A or anti-CD3. H1.2F3 is a potent stimulator of T, but not B, cell proliferation in the presence of PMA and FcR-bearing accessory cells. These functional and biochemical studies strongly suggest that the Ag recognized by H1.2F3 is the murine homologue of the human CD28 Ag recognized by mAb 9.3.
MeSH Terms
- Aging
- Animals
- Antibodies, Monoclonal
- Antigen-Presenting Cells
- Antigens, Surface
- Cricetinae
- Disulfides
- Lymphocyte Activation
- Mice
- Mice, Inbred C3H
- Molecular Weight
- Protein Conformation
- Structure-Activity Relationship
- T-Lymphocytes
- Tetradecanoylphorbol Acetate
- Tumor Necrosis Factor Receptor Superfamily, Member 7
Recent studies have focused on the potential role of accessory molecules such as CD2, CD28, Thy-1, or TAP in the delivery of activating signals to thymocytes through antigen-independent pathways. To better understand the molecular interactions involved in the expansion of early thymic immigrants, rat mAb were raised against murine thymocyte-surface molecules and screened for their capacity to trigger thymocyte proliferation. One of these mAb (H194-112, IgG2a) was found to recognize a novel heterodimeric thymocyte-activating molecule (THAM) of Mr = 110,000 to 128,000. Flow cytometric analyses and staining patterns on frozen thymus sections subdivided adult thymocytes in three subsets expressing THAM at either low (10%), moderate (80%), or high (5 to 8%) cell-surface density; these cell groups were found to correspond, respectively, to the medullary, the cortical, and the immature CD4-CD8-, J11d thymocytes, in which the T cell precursor pool is included. Moreover, most (90%) day 16 fetal thymocytes were also found to upregulate THAM cell-surface expression. The THAMhigh cells were localized in the subcapsular area of the neonatal thymus and scattered throughout the adult organ. Cross-linked mAb H194-112 induced the proliferation of both immature and mature thymocytes in the presence of either PMA or IL-1 and IL-2. The observation that early thymocytes up-regulate THAM along with the IL-2R suggests that this molecule might be involved in an important activation pathway during thymocyte differentiation.
MeSH Terms
- Aging
- Animals
- Antibodies, Monoclonal
- Antigens, CD
- Antigens, Differentiation, T-Lymphocyte
- Epitopes
- Interleukin-2
- Lectins, C-Type
- Lymphocyte Activation
- Mice
- Mice, Inbred BALB C
- Phenotype
- Rats
- T-Lymphocytes
- Thymoma
- Thymus Gland