CCR7
C-C chemokine receptor type 7 precursor (C-C CKR-7) (CC-CKR-7) (CCR-7) (BLR2) (CDw197) (Epstein-Barr virus-induced G-protein coupled receptor 1) (EBI1) (EBV-induced G-protein coupled receptor 1) (MIP-3 beta receptor) (CD197 antigen) [CMKBR7] [EBI1] [EVI1]
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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
The number of aging cancer patients has increased continuously and will do so further in the future. The immune system of elderly people experiences critical changes over the time. Therefore, tumor-induced changes in the immune system are believed to differ in young and elderly cancer patients as well. The effect of aging on the immune system was measured in peripheral blood lymphocytes (PBL) of healthy volunteers ([i]n[/i] = 48, 21-84 yrs.) divided into three different age groups. Seventy years was set as a cut-off for defining subjects as elderly. Results were compared to two groups of adult cancer patients, which donated PBL and tumor infiltrating lymphocytes (TIL): young cancer patients (40-69 yrs.; blood: [i]n[/i] = 13; TIL: [i]n[/i] = 17) and elderly cancer patients (70-90 yrs.; blood: [i]n[/i] = 20; TIL: [i]n[/i] = 15) with head and neck squamous cell carcinoma (HNSCC). Frequencies and phenotypes of CD4 and CD8 T cells as well as regulatory T cells (T ) were assessed by flow cytometry. We observed lower frequencies of CD8 cytotoxic T cells during aging in both groups. Frequencies of tumor infiltrating regulatory T cells were significantly higher than in the peripheral blood but showed a significant decline in older tumor patients. With increasing age, expression of immunosuppressive CD73 and CCR7 was lower and expression of PD1 elevated on peripheral T cells in healthy volunteers and tumor patients. Immunosenescence takes place in healthy donors and cancer patients. Our results suggest that in elderly tumor patients, the immune system is impaired and the tumor-induced immune escape is less pronounced. The increased expression of PD1 implies the potential for effective immunotherapies in elderly, as treatment with checkpoint inhibitors could be more beneficial for elderly HNSCC patients.
Keywords
- Aging
- Head and neck cancer
- Immune escape
- Immunosenescence
- T cells
Our study objective was to explore whether abnormalities in the subtypes of T cells and B cells were present in peripheral blood of patients with osteoarthritis (OA) and healthy controls (HCs). Demographic and clinical variables and blood were collected. OA severity was measured using the Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) questionnaire. Flow cytometry was used to establish the frequencies of lineage subsets. Monoclonal antibodies against 21 surface markers were used to distinguish and evaluate T cells' and B cells' subpopulation. The proportion of each subset was compared and correlations between age, immune cells, and clinical data were analyzed. A total of 30 OA patients (male/female = 9/21) and 45 HCs (male/female = 14/31) were included. Median WOMAC pain was 3.0 (2.0). There was no difference in the proportion of T cells, CD8 T cells, and B cells (p > 0.05). The proportion of CD4 T cells was higher in OA groups, together with an increased CD4 to CD8 ratio (p = 0.016). CD8 CD45RA T cells were reduced after adjustment for age, while CD8 CD45RA- T cells were elevated in OA (p < 0.05). CD4 CD45RA-CCR7 T cells and CD4 CD45RA-CCR7- T cells were increased (p < 0.004). The proportion of T helper (Th) 17 and T follicular helper (Tfh) 2 cells was higher, but cytotoxic T (Tc) 17 cells were fewer in OA (p < 0.05). CD3-CD19 IgD-IgM-CD27 CD38 B cells were decreased in OA (p ≤ 0.001). The WOMAC pain score correlated with CD3 CD4 CXCR5-PD-1 T cells positively (B = 0.404, p = 0.027). CD3-CD19 CD27-IgD cells correlated negatively with erythrocyte sedimentation rate (ESR) (B = -0.550, p = 0.005). The T cell and B cell profiles were proved to have alteration suggesting that acquired immune system may play a substantial role in the pathogenesis of OA.Key Points• The T cell and B cell profiles were proved to have alteration suggesting that acquired immune system may play a substantial role in the pathogenesis of OA.• The WOMAC pain score correlated with CD3 CD4 CXCR5-PD-1 T cells and T helper 17 cells positively.• Memory T cells were increased in OA patients, suggesting they could play an important role in OA.
MeSH Terms
- Aged
- Aging
- B-Lymphocyte Subsets
- Case-Control Studies
- Female
- Humans
- Male
- Middle Aged
- Osteoarthritis, Knee
- T-Lymphocyte Subsets
Keywords
- B cell
- Lymphocyte
- Osteoarthritis
- T cell
How lymphoma cells (LCs) invade the brain during the development of central nervous system lymphoma (CNSL) is unclear. We found that NF-κB-induced gliosis promotes CNSL in immunocompetent mice. Gliosis elevated cell-adhesion molecules, which increased LCs in the brain but was insufficient to induce CNSL. Astrocyte-derived CCL19 was required for gliosis-induced CNSL. Deleting CCL19 in mice or CCR7 from LCs abrogated CNSL development. Two-photon microscopy revealed LCs transiently entering normal brain parenchyma. Astrocytic CCL19 enhanced parenchymal CNS retention of LCs, thereby promoting CNSL formation. Aged, gliotic wild-type mice were more susceptible to forming CNSL than young wild-type mice, and astrocytic CCL19 was observed in both human gliosis and CNSL. Therefore, CCL19-CCR7 interactions may underlie an increased age-related risk for CNSL.
MeSH Terms
- Adolescent
- Adult
- Aged
- Aging
- Animals
- Astrocytes
- Blood-Brain Barrier
- Cell Line, Tumor
- Central Nervous System Neoplasms
- Chemokine CCL19
- Chemokine CXCL12
- Disease Models, Animal
- Female
- Gliosis
- Humans
- Intravital Microscopy
- Lymphoma
- Male
- Mice
- Mice, Transgenic
- Microscopy, Fluorescence, Multiphoton
- Middle Aged
- NF-kappa B
- Receptors, CCR7
- Time-Lapse Imaging
- Young Adult
Keywords
- CCL19
- CNSL
- CXCL12
- DLBCL
- PCNSL
- SCNSL
- gliosis
- lymphoma
- metastasis
- neuroinflammation
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
Juvenile tissue healing is capable of extensive scarless healing that is distinct from the scar-forming process of the adult healing response. Although many growth factors can be found in the juvenile healing process, the molecular mechanisms of juvenile tissue healing are poorly understood. Here we show that juvenile mice deficient in the chemokine receptor CCR7 exhibit diminished large-scale healing potential, whereas CCR7-depleted adult mice undergo normal scar-forming healing similar to wild type mice. In addition, the CCR7 ligand CCL21 was transiently expressed around damaged cartilage in juvenile mice, whereas it is rarely expressed in adults. Notably, exogenous CCL21 administration to adults decreased scar-forming healing and enhanced hyaline-cartilage repair in rabbit osteochondral defects. Our data indicate that the CCL21/CCR7 axis may play a role in the molecular control mechanism of juvenile cartilage repair, raising the possibility that agents modulating the production of CCL21 in vivo can improve the quality of cartilage repair in adults. Such a strategy may prevent post-traumatic arthritis by mimicking the self-repair in juvenile individuals.
MeSH Terms
- Aging
- Animals
- Bone and Bones
- Cartilage
- Cell Differentiation
- Cell Movement
- Cells, Cultured
- Chemokine CCL21
- Chondrocytes
- Chondrogenesis
- Female
- Mesenchymal Stem Cells
- Mice, Inbred C57BL
- Rabbits
- Receptors, CCR7
- Signal Transduction
- Wound Healing
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
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
Ageing has profound impact on the immune system, mainly on T-cells. However, it has been suggested that chronic exercise may delay immunosenescence. Master athletes represent an interesting sub-demographic group to test this theory since they maintain a high training frequency and load throughout life. The purpose of this study was to evaluate the effects of lifelong training on the senescence and mobilization of T lymphocytes in response to acute exercise. Nineteen athletes who regularly participated in training and competitions for more than 20 years throughout their lives and a control group of 10 healthy individuals participated in this study. All subjects performed a progressive test to exhaustion on a cycle ergometer. Blood samples were obtained before (Pre), 10 min after the test (Post) and 1 h after the test (1h). Phenotypic study of peripheral blood T-cells was performed by flow cytometry. Genes of interest expression was done on T-cells purified by cell sorting. Master athletes had a lower percentage of senescent naïve, central memory and effector memory CD8 T-cells and senescent naïve and effector memory CD4 T-cells. Age had a positive effect on SLEC CD8 T-cells and a negative effect on naïve CD8 T-cells. VO2max positively correlated with the proportion of naïve CD4 T-cells and negatively correlated with the percentage of total lymphocytes. No differences were founded for CD4 and CD8 T-cells and their subsets between master athletes and the control group at all times of measurement. No differences were observed in the CD45RA expressing effector memory cells (EMRA) for the various study conditions. The mRNA expression of the CCR7 gene for naïve CD8 T-cells and the Fas-L gene for effector-terminal CD8 T-cells was not different between masters and controls and did not change in response to the maximal protocol test. In conclusion, maintaining high levels of aerobic fitness during the natural course of aging may help prevent the accumulation of senescent T-cells.
MeSH Terms
- Athletes
- CD4-Positive T-Lymphocytes
- CD8-Positive T-Lymphocytes
- Cell Separation
- Exercise
- Female
- Flow Cytometry
- Humans
- Immunologic Memory
- Immunosenescence
- Male
- Middle Aged
- Oxygen Consumption
- T-Lymphocyte Subsets
Keywords
- CCR7
- Cytomegalovirus
- Fas-L
- Immune space
- Immunosenescence
- KLRG1
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
Dendritic cells (DCs) are antigen-presenting cells that critically influence decisions about immune activation or tolerance. Impaired DC function is at the core of common chronic disorders and contributes to reduce immunocompetence during aging. Knowledge on the mechanisms regulating DC generation and function is necessary to understand the immune system and to prevent disease and immunosenescence. Here we show that the sirtuin Sirt6, which was previously linked to healthspan promotion, stimulates the development of myeloid, conventional DCs (cDCs). Sirt6-knockout (Sirt6KO) mice exhibit low frequencies of bone marrow cDC precursors and low yields of bone marrow-derived cDCs compared to wild-type (WT) animals. Sirt6KO cDCs express lower levels of class II MHC, of costimulatory molecules, and of the chemokine receptor CCR7, and are less immunostimulatory compared to WT cDCs. Similar effects in terms of differentiation and immunostimulatory capacity were observed in human monocyte-derived DCs in response to SIRT6 inhibition. Finally, while Sirt6KO cDCs show an overall reduction in their ability to produce IL-12, TNF-α and IL-6 secretion varies dependent on the stimulus, being reduced in response to CpG, but increased in response to other Toll-like receptor ligands. In conclusion, Sirt6 plays a crucial role in cDC differentiation and function and reduced Sirt6 activity may contribute to immunosenescence.
MeSH Terms
- Animals
- Cell Differentiation
- Cell Lineage
- Cells, Cultured
- Dendritic Cells
- Genotype
- Histocompatibility Antigens Class II
- Histone Deacetylase Inhibitors
- Immunosenescence
- Interleukin-12
- Interleukin-6
- Mice, 129 Strain
- Mice, Inbred BALB C
- Mice, Knockout
- Phenotype
- Receptors, CCR7
- Sirtuins
- Toll-Like Receptors
- Tumor Necrosis Factor-alpha
Keywords
- Sirt6
- TNF-α
- Toll-like receptor ligands
- costimulatory molecules
- dendritic cells
- immunosenescence
Recent evidence has determined a phenotypic and functional heterogeneity for macrophage populations. This plasticity of macrophage function has been related to specific properties of subsets (M1 and M2) of these cells in inflammation, adaptive immune responses and resolution of tissue destructive processes. This investigation hypothesized that targeted alterations in the distribution of macrophage phenotypes in aged individuals, and with periodontitis would be skewed towards M1 inflammatory macrophages in gingival tissues. The study used a non-human primate model to evaluate gene expression profiles as footprints of macrophage variation in healthy and periodontitis gingival tissues from animals 3-23 years of age and in periodontitis tissues in adult and aged animals. Significant increases in multiple genes reflecting overall increases in macrophage activities were observed in healthy aged tissues, and were significantly increased in periodontitis tissues from both adults and aged animals. Generally, gene expression patterns for M2 macrophages were similar in healthy young, adolescent and adult tissues. However, modest increases were noted in healthy aged tissues, similar to those seen in periodontitis tissues from both age groups. M1 macrophage gene transcription patterns increased significantly over the age range in healthy tissues, with multiple genes (e.g. CCL13, CCL19, CCR7 and TLR4) significantly increased in aged animals. Additionally, gene expression patterns for M1 macrophages were significantly increased in adult health versus periodontitis and aged healthy versus periodontitis. The findings supported a significant increase in macrophages with aging and in periodontitis. The primary increases in both healthy aged tissues and, particularly periodontitis tissues appeared in the M1 phenotype.
MeSH Terms
- Age Factors
- Aging
- Animals
- Disease Models, Animal
- Female
- Gene Expression Profiling
- Gene Expression Regulation
- Gingiva
- Macaca mulatta
- Macrophage Activation
- Macrophages
- Male
- Periodontitis
- Transcriptome
Keywords
- Aging
- gene expression
- gingival tissue
- macrophage polarization
- periodontitis
Human ageing affects the immune system resulting in an overall decline in immunocompetence. Although all immune cells are affected during aging, the functional capacity of T cells is most influenced and is linked to decreased responsiveness to infections and impaired differentiation. We studied age-related changes in DNA methylation and gene expression in CD4 and CD8 T cells from younger and older individuals. We observed marked difference between T cell subsets, with increased number of methylation changes and higher methylome variation in CD8 T cells with age. The majority of age-related hypermethylated sites were located at CpG islands of silent genes and enriched for repressive histone marks. Specifically, in CD8 T cell subset we identified strong inverse correlation between methylation and expression levels in genes associated with T cell mediated immune response (LGALS1, IFNG, CCL5, GZMH, CCR7, CD27 and CD248) and differentiation (SATB1, TCF7, BCL11B and RUNX3). Our results thus suggest the link between age-related epigenetic changes and impaired T cell function.
MeSH Terms
- Adult
- Aged
- Aged, 80 and over
- Aging
- CD4-Positive T-Lymphocytes
- CD8-Positive T-Lymphocytes
- Cell Differentiation
- Cell Lineage
- CpG Islands
- DNA Methylation
- Gene Expression Regulation
- Histone Code
- Humans
- Immunity
- Middle Aged
- Transcription, Genetic
- Young Adult
In addition to the secretion of Ag-specific Abs, B cells may play an important role in the generation of immune responses by efficiently presenting Ag to T cells. We and other investigators recently described a subpopulation of CD11c( ) B cells (Age/autoimmune-associated B cells [ABCs]) that appear with age, during virus infections, and at the onset of some autoimmune diseases and participate in autoimmune responses by secreting autoantibodies. In this study, we assessed the ability of these cells to present Ag and activate Ag-specific T cells. We demonstrated that ABCs present Ag to T cells, in vitro and in vivo, better than do follicular B cells (FO cells). Our data indicate that ABCs express higher levels of the chemokine receptor CCR7, have higher responsiveness to CCL21 and CCL19 than do FO cells, and are localized at the T/B cell border in spleen. Using multiphoton microscopy, we show that, in vivo, CD11c( ) B cells form significantly more stable interactions with T cells than do FO cells. Together, these data identify a previously undescribed role for ABCs as potent APCs and suggest another potential mechanism by which these cells can influence immune responses and/or the development of autoimmunity.
MeSH Terms
- Aging
- Animals
- Antigen-Presenting Cells
- Autoantibodies
- Autoimmunity
- B-Lymphocytes
- CD11c Antigen
- Chemokine CCL19
- Chemokine CCL21
- Female
- Gene Expression Regulation
- Mice
- Mice, Inbred C57BL
- Receptors, CCR7
- Signal Transduction
- Spleen
- T-Lymphocytes
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
The impairment of humoral immune response in elderly humans has been extensively demonstrated. We have reported the increase of memory B cells (IgG( )IgD(-)CD27(-), double negative, DN) population in the elderly, in which there is also a typical inflammatory micro-environment. In order to evaluate whether this pro-inflammatory status could influence the trafficking phenotype of naïve/memory B cells, we have assessed the expression of CCR7, CCR6, CXCR3, CXCR4, CXCR5 and CD62L on naïve/memory B cell subpopulations in young and elderly subjects. Moreover, the combination of pro-inflammatory interleukin-21 (IL-21) and B cell receptor (BCR) stimulation enables B cells to produce and secrete granzyme B (GrB), which plays a critical role in early anti-viral immune responses, in the regulation of autoimmune mechanisms and in cancer immunosurveillance. Our data demonstrate that in the elderly, naïve/memory B cell populations present a different expression of the studied receptors that could be discussed in terms of "inflamm-aging". In particular IgG( )IgD(-)CD27(-) DN B cells show a tissue trafficking phenotype and they can be stimulated to produce GrB.
MeSH Terms
- Adult
- Aged
- Aged, 80 and over
- Aging
- B-Lymphocyte Subsets
- Granzymes
- Humans
- Immunoglobulin D
- Immunoglobulin G
- Interleukins
- L-Selectin
- Phenotype
- Receptors, CXCR
- Tumor Necrosis Factor Receptor Superfamily, Member 7
Keywords
- B lymphocytes
- Chemokine receptors
- Elderly
- Granzyme B
- IL-21
- Inflamm-aging
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
Dendritic cells (DCs) are critical for the generation of T-cell responses. DC function may be modulated by probiotics, which confer health benefits in immunocompromised individuals, such as the elderly. This study investigated the effects of four probiotics, Bifidobacterium longum bv. infantis CCUG 52486, B. longum SP 07/3, Lactobacillus rhamnosus GG (L.GG) and L. casei Shirota (LcS), on DC function in an allogeneic mixed leucocyte reaction (MLR) model, using DCs and T-cells from young and older donors in different combinations. All four probiotics enhanced expression of CD40, CD80 and CCR7 on both young and older DCs, but enhanced cytokine production (TGF-β, TNF-α) by old DCs only. LcS induced IL-12 and IFNγ production by DC to a greater degree than other strains, while B. longum bv. infantis CCUG 52486 favoured IL-10 production. Stimulation of young T cells in an allogeneic MLR with DC was enhanced by probiotic pretreatment of old DCs, which demonstrated greater activation (CD25) than untreated controls. However, pretreatment of young or old DCs with LPS or probiotics failed to enhance the proliferation of T-cells derived from older donors. In conclusion, this study demonstrates that ageing increases the responsiveness of DCs to probiotics, but this is not sufficient to overcome the impact of immunosenescence in the MLR.
MeSH Terms
- Adult
- Aged
- Aging
- Antigen Presentation
- Antigens, CD
- Bifidobacterium
- Cell Differentiation
- Cell Proliferation
- Cells, Cultured
- Cytokines
- Dendritic Cells
- Humans
- Isoantigens
- Lactobacillus casei
- Lactobacillus rhamnosus
- Lymphocyte Activation
- Lymphocyte Culture Test, Mixed
- Male
- Probiotics
- Receptors, CCR7
- T-Lymphocytes
- Young Adult
Keywords
- Ageing
- Allogeneic mixed leucocyte reaction
- CFSE
- Cytokine
- DCs
- Dendritic cells
- L. casei Shirota
- LcS
- MLR
- PAMPs
- PRPs
- Probiotics
- carboxyfluorescein diacetate succinimidyl ester
- dendritic cells
- mixed leucocyte reaction
- pathogen recognition patterns
- pathogen-associated molecular patterns