CD27
CD27 antigen precursor (CD27L receptor) (T-cell activation antigen CD27) (T14) (Tumor necrosis factor receptor superfamily member 7) [TNFRSF7]
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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 Nijmegen Breakage Syndrome (NBS) suffer from recurrent infections due to humoral and cellular immune deficiency. Despite low number of T lymphocytes and their maturation defect, the clinical manifestations of cell-mediated deficiency are not as severe as in case of patients with other types of combined immune deficiencies and similar T cell lymphopenia. In this study, multicolor flow cytometry was used for evaluation of peripheral T lymphocyte maturation according to the currently known differentiation pathway, in 46 patients with genetically confirmed NBS and 46 sex and age-matched controls. Evaluation of differential expression of CD27, CD31, CD45RA, CD95, and CD197 revealed existence of cell subsets so far not described in NBS patients. Although recent thymic emigrants and naïve T lymphocyte cell populations were significantly lower, the generation of antigen-primed T cells was similar or even greater in NBS patients than in healthy controls. Moreover, the senescent and exhausted T cell populations defined by expression of CD57, KLRG1, and PD1 were more numerous than in healthy people. Although this hypothesis needs further investigations, such properties might be related to an increased susceptibility to malignancy and milder clinical course than expected in view of T cell lymphopenia in patients with NBS.
Keywords
- Nijmegen Breakage Syndrome
- T lymphocyte maturation
- flow cytometry
- immune exhaustion
- immune senescence
- primary immune deficiency
The social, health, and economic challenges of a steadily increasing aging population demand the use of appropriate translational animal models to address questions like healthy aging, vaccination strategies, or potential interventions during the aging process. Due to their genetic proximity to humans, especially nonhuman primates (NHPs) with a relatively short generation period compared to humans, qualify as excellent animal models for these purposes. The use of common marmosets (Callithrix jacchus) in gerontology research steadily increased over the last decades, yet important information about their aging parameters are still missing. We therefore aimed to characterize their aging immune system by comprehensive flow cytometric phenotyping of blood immune cells from juvenile, adult, aging, and geriatric animals. Aged and geriatric animals displayed clear signs of immunosenescence. A decline in CD4/CD8 ratio, increased expression of HLA-DR and PD-1, higher frequencies of CD95 memory cells, alterations in cytokine secretion, and a decline in the proliferative capacity proved T cell senescence in aging marmosets. Also, the B cell compartment was affected by age-related changes: while overall B cell numbers remained stable with advancing age, expression of the activation marker CD80 increased and immunoglobulin M expression decreased. Interestingly, marmoset B cell memory subset distribution rather mirrored the human situation than that of other NHP. CD21 CD27 naïve B cell frequencies decreased while those of CD21 CD27 tissue memory B cells increased with age. Furthermore, frequencies and numbers of NK cells as part of the innate immune system declined with advancing age. Thus, the observed immunological changes in common marmosets over their life span revealed several similarities to age-related changes in humans and encourages further studies to strengthen the common marmoset as a potential aging model.
MeSH Terms
- Aging
- Animals
- CD4-CD8 Ratio
- Callithrix
- Female
- Flow Cytometry
- Immune System
- Longevity
- Male
- Models, Animal
- Sex Factors
Keywords
- aging
- common marmoset
- immune system
- immunosenescence
- innate and adaptive immunity
- sex
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
Memory B cells (MBCs) epitomize the adaptation of the immune system to the environment. We identify two MBC subsets in peripheral blood, CD27 and CD27 MBCs, whose frequency changes with age. Heavy chain variable region (VH) usage, somatic mutation frequency replacement-to-silent ratio, and CDR3 property changes, reflecting consecutive selection of highly antigen-specific, low cross-reactive antibody variants, all demonstrate that CD27 and CD27 MBCs represent sequential MBC developmental stages, and stringent antigen-driven pressure selects CD27 into the CD27 MBC pool. Dynamics of human MBCs are exploited in pregnancy, when 50% of maternal MBCs are lost and CD27 MBCs transit to the more differentiated CD27 stage. In the postpartum period, the maternal MBC pool is replenished by the expansion of persistent CD27 clones. Thus, the stability and flexibility of human B cell memory is ensured by CD27 MBCs that expand and differentiate in response to change.
Keywords
- CD27
- VH repertoire
- aging
- germinal center
- immunodeficiency
- immunological memory
- memory B cells
- pregnancy
- spleen
- vaccine
Cytomegalovirus (CMV) seropositivity in adults has been linked to increased cardiovascular disease burden. Phenotypically, CMV infection leads to an inflated CD8 T-lymphocyte compartment. We employed a 8-colour flow cytometric protocol to analyse circulating T cells in 597 octogenarians from the same birth cohort together with NT-proBNP measurements and followed all participants over 7 years. We found that, independent of CMV serostatus, a high number of CD27-CD28 CD8 EMRA T-lymphocytes (TEMRA) protected from all-cause death after adjusting for known risk factors, such as heart failure, frailty or cancer (Hazard ratio 0.66 for highest vs lowest tertile; confidence interval 0.51-0.86). In addition, CD27-CD28 CD8 EMRA T-lymphocytes protected from both, non-cardiovascular (hazard ratio 0.59) and cardiovascular death (hazard ratio 0.65). In aged mice treated with the senolytic navitoclax, in which we have previously shown a rejuvenated cardiac phenotype, CD8 effector memory cells are decreased, further indicating that alterations in T cell subpopulations are associated with cardiovascular ageing. Future studies are required to show whether targeting immunosenescence will lead to enhanced life- or healthspan.
Keywords
- Biomarkers
- Senescence
Cytotoxic activity mediated by CD8 T cells is the main signature of the immunopathogenesis of cutaneous leishmaniasis (CL). Here, we performed a broad evaluation of natural killer (NK) cell phenotypic and functional features during cutaneous leishmaniasis. We demonstrate for the first time that CL patients present the accumulation of circulating NK cells with multiple features of replicative senescence including low proliferative capacity and shorter telomeres, elevated expression of CD57, KLRG1 but diminished CD27 stimulatory receptor expression. Moreover, they exhibited higher cytotoxic and inflammatory potential than age-matched controls. The accumulation of circulating senescent NK cells (CD56 CD57 ) correlated positively with skin lesion size in the same patients, suggesting that they, like circulating senescent CD8 T cells, may contribute to the immunopathology of CL. However, this senescent population had lower cutaneous lymphocyte antigen expression and so had diminished skin-homing potential compared with total or senescent CD8 T cells. This was confirmed in CL skin lesions where we found a predominance of CD8 T cells (both senescent and non-senescent) that correlated with the severity of the disease. Although there was also a correlation between the proportions of senescent NK cells (CD56 CD57 ) in the skin and lesion size, this was less evident. Collectively our results demonstrate first-hand that senescent cytotoxic cells may mediate skin pathology during human cutaneous leishmaniasis. However, as senescent cytotoxic CD8 T cells predominate in the skin lesions, they may have a greater role than NK cells in mediating the non-specific skin damage in CL.
MeSH Terms
- CD56 Antigen
- CD57 Antigens
- Case-Control Studies
- Cellular Senescence
- Cytotoxicity, Immunologic
- Female
- Gene Expression Regulation
- Host-Parasite Interactions
- Humans
- Interferon-gamma
- Killer Cells, Natural
- Lectins, C-Type
- Leishmania braziliensis
- Leishmaniasis, Cutaneous
- Male
- Oligosaccharides
- Receptors, Immunologic
- Severity of Illness Index
- Sialyl Lewis X Antigen
- Signal Transduction
- Skin
- T-Lymphocytes, Cytotoxic
Keywords
Leishmania braziliensis
- CD8 T cells
- cellular senescence
- cutaneous leishmaniasis
- immunopathology
- natural killer cells
Immunosenescence, i.e. the aging-associated decline of the capacity of the immune system, is characterized by several distinct changes in the number and functions of the immune cells. In the case of B cells, the total number of CD19 B cells is lower in the blood of elderly individuals than in the younger ones. CD19 B cell population contains several subsets, which are commonly characterized by the presence of CD27 and IgD molecules, i.e. naïve B cells (CD27- IgD ), IgM memory (CD27 IgD ), switched memory (CD27 IgD-) and late memory (CD27- IgD-). This late memory, double negative, population represents cells which are nondividing, but are still able to produce inflammatory mediators and in this way maybe contributing to the aging-associated inflammation, inflammaging. Here we have focused on the role of these B cell subsets in elderly individuals, nonagenarians, in the regulation of inflammation and inflammation-associated decline of bodily functions. As the biological aging process demonstrates gender-specific characteristics, the analyses were performed separately in males and female. A subcohort of The Vitality 90 study (67 nonagenarians, 22/45 males/females and 40 young controls, 13/27 males/females) was used. Flow cytometric analysis indicated that the total percentage of the CD19 cells was ca. 50% lower in the nonagenarians than in the controls in both genders. The proportions of these four B cell subsets within the CD19 populations were very similar in young and old individuals. Thus, it seems that the aging-associated decline of the total CD19 cells affects similarly all these B cell subsets. To analyze the role of these subsets in the regulation of inflammation, the correlation with IL-6 levels was calculated. A significant correlation was observed only with the percentage of CD27- IgD- cells and only in males. As inflammation is associated with aging-associated functional performance and frailty, the correlations with the Barthel index and frailty score was analyzed. Again, only the CD27- IgD- population demonstrated a strong male-specific correlation. These data show that the CD27- IgD- B cell subset demonstrates a strong pro-inflammatory effect in nonagenarians, which significantly associates with the decline of the bodily functions. However, this phenomenon is only observed in males.
Keywords
- Aging
- B cell
- Frailty
- Immunosenescence
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
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
[i]Leishmania (Viannia) braziliensis[/i] induces American tegumentary leishmaniasis that ranges in severity from the milder form, cutaneous (CL) to severe disseminated cutaneous leishmaniasis. Patients with CL develop a cell-mediated Th1 immune response accompanied by production of inflammatory cytokines, which contribute to parasite control and pathogenesis of disease. Here, we describe the accumulation of circulating T cells with multiple features of telomere dependent-senescence including elevated expression of CD57, KLRG-1, and γH2AX that have short telomeres and low hTERT expression during cutaneous [i]L. braziliensis[/i] infection. This expanded population of T cells was found within the CD45RA CD27 (EMRA) subset and produced high levels of inflammatory cytokines, analogous to the senescence-associated secretory profile (SASP) that has been described in senescent non-lymphoid cells. There was a significant correlation between the accumulation of these cells and the extent of systemic inflammation, suggesting that they are involved in the inflammatory response in this disease. Furthermore, these cells expressed high level of the skin homing receptor CLA and there was a highly significant correlation between the number of these cells in the circulation and the size of the [i]Leishmania[/i]-induced lesions in the skin. Collectively our results suggest that extensive activation during the early stages of leishmaniasis drives the senescence of T cells with the propensity to home to the skin. The senescence-related inflammatory cytokine secretion by these cells may control the infection but also contribute to the immunopathology in the disease.
MeSH Terms
- Adult
- Cellular Senescence
- Cytokines
- Female
- Humans
- Inflammation
- Leishmania braziliensis
- Leishmaniasis, Cutaneous
- Male
- Middle Aged
- Receptors, Lymphocyte Homing
- Skin
- T-Lymphocytes
- Young Adult
Keywords
- L. braziliensis
- SASP-analogous
- T cells
- cutaneous leishmaniasis
- immunosenescence
- inflammation
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
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
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
Calorie restriction (CR), also known as energy restriction, has been shown to have a deleterious impact on both adult and aged mouse survival during influenza virus infection. Natural killer (NK) cell phenotypic differences contribute to increased susceptibility of adult CR mice. We hypothesized NK cell phenotype from adult and aged C57Bl/6 mice fed NIH-31 diet ad libitum (AL) would be different from NK cell phenotype from adult and aged mice fed NIH-31/NIA fortified diet at 40% CR. We hypothesized NK cell phenotype from mice consuming 40% CR initiated at 20 months of age would not be different from 40% CR initiated at 3 months of age. We initiated the 40% restriction either at the standard 12 weeks of age or at 78 weeks of age. NK cells were isolated and quantified from various tissues using flow cytometry. Aged CR mice had significantly reduced levels of terminally mature (CD27 CD11b ) NK cells, increased expression of the immature marker CD127, and decreased expression of the mature marker DX5. Total number of NK cells among cells was significantly lower in the lung and spleen of old-onset aged CR mice compared to aged AL mice, while there was no significant difference between young-onset aged CR and aged AL mice. Old-onset aged CR mice had significantly less early mature (DX5 and CD27 CD11b ) NK cells compared to young-onset aged CR and aged AL fed mice. Overall, we found that CR in aged mice is detrimental to maturation of NK cells, which is exacerbated when CR is initiated in old age.
MeSH Terms
- Age Factors
- Aging
- Animals
- CD11 Antigens
- Caloric Restriction
- Energy Intake
- Flow Cytometry
- Interleukin-7 Receptor alpha Subunit
- Killer Cells, Natural
- Lung
- Male
- Mice, Inbred C57BL
- Spleen
- Tumor Necrosis Factor Receptor Superfamily, Member 7
Keywords
- Aging
- Calorie restriction
- Cell maturation
- Mice
- Natural killer cell
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
The study aims to generate an immunological age (IA) trait on the basis of immune cell differentiation parameters, and to test whether the IA is related to age and disease characteristics. Forty-four euthymic type I bipolar disorder patients were included in this study. Five immunosenescence-related parameters were assessed: proportions of late-differentiated cells (e.g., CD3 CD8 CD28-CD27- and CD3-CD19 IgD-CD27-), and the expression of CD69, CD71, and CD152 after stimulation. Confirmatory factor analysis was applied to generate an IA trait underling the 5 measures. The best-fit model was constituted by 4 parameters that were each related to an underlying IA trait, with 1 cell population positively correlated (CD3 CD8 CD28-CD27- [λ = 0.544, where λ represents the loading of the parameter onto the IA trait] and 3 markers negatively correlated (CD69 [λ = -0.488], CD71 [λ = -0.833], and CD152 [λ = -0.674]). The IA trait was associated with chronological age (β = 0.360, p = .013) and the number of previous mood episodes (β = 0.426, p = .006). In a mediation model, 84% of the effect between manic episodes, and IA was mediated by body mass index. In bipolar disorder type I, premature aging of the immune system could be reliably measured using an index that validated against chronological age, which was related to adverse metabolic effects of the disease course.
MeSH Terms
- Adolescent
- Adult
- Aging, Premature
- Biomarkers
- Bipolar Disorder
- Factor Analysis, Statistical
- Female
- Humans
- Immunosenescence
- Male
- Middle Aged
- Young Adult
Keywords
- aging
- bipolar
- confirmatory factor analysis
- neuroimmunology
Humoral immunocompetence develops stepwise throughout life and contributes to individual susceptibility to infection, immunodeficiency, autoimmunity, and neoplasia. Immunoglobulin heavy chain (IgH) isotype serum levels can partly explain such age-related differences, but their relationship with the IgH isotype distribution within memory B-cell (MBC) and plasma cell (PCs) compartments remains to be investigated. We studied the age-related distribution of MBCs and PCs expressing different IgH isotypes in addition to the immature/transitional and naive B-cell compartments. B-cell and PC subsets and plasma IgH isotype levels were studied in cord blood (n = 19) and peripheral blood (n = 215) from healthy donors aged 0 to 90 years by using flow cytometry and nephelometry, respectively. IgH-switched MBCs expressing IgG , IgG , IgG , IgA , and IgA were already detected in cord blood and newborns at very low counts, whereas CD27 IgM IgD MBCs only became detectable at 1 to 5 months and remained stable until 2 to 4 years, and IgD MBCs peaked at 2 to 4 years, with both populations decreasing thereafter. MBCs expressing IgH isotypes of the second immunoglobulin heavy chain constant region (IGHC) gene block (IgG , IgG , and IgA ) peaked later during childhood (2-4 years), whereas MBCs expressing third IGHC gene block immunoglobulin isotypes (IgG , IgG , and IgA ) reached maximum values during adulthood. PCs were already detected in newborns, increasing in number until 6 to 11 months for IgM, IgG , IgG , IgG , IgA , and IgA ; until 2 to 4 years for IgD; and until 5 to 9 years for IgG and decreasing thereafter. For most IgH isotypes (except IgD and IgG ), maximum plasma levels were reached after PC and MBC counts peaked. PC counts reach maximum values early in life, followed by MBC counts and plasma IgH isotypes. Importantly, IgH isotypes from different IGHC gene blocks show different patterns, probably reflecting consecutive cycles of IgH isotype switch recombination through life.
MeSH Terms
- Adolescent
- Adult
- Aged
- Aged, 80 and over
- Aging
- B-Lymphocytes
- Child
- Child, Preschool
- Female
- Humans
- Immunity, Humoral
- Immunoglobulin Class Switching
- Immunoglobulin Heavy Chains
- Immunoglobulin Isotypes
- Immunologic Memory
- Infant
- Infant, Newborn
- Male
- Middle Aged
- Plasma Cells
- Young Adult
Keywords
- IgH isotype
- Immunoglobulins
- age-related values
- flow cytometry
- memory B cells
- normal B cells
- plasma cells
- reference ranges
- subclass
Individuals over the age of 65 comprise a substantial portion of the world population and become more susceptible to vaccine-preventable infections with age as vaccination response diminishes. The underlying reason for this impaired vaccine response in older individuals is not entirely clear. We evaluated potential differences in phenotypic and functional responses of B cells from healthy younger (22-45years) and older (64-95years) individuals that may associate with a diminished antibody response to influenza vaccination. We report that age is associated with expansion of atypical memory B cells (CD10 CD20 CD21 CD27 ) and an age-associated B cell (ABC, CD21 T-bet CD11c ) phenotype. Reduced expression of PAX5 was also seen in older individuals. Poor influenza-specific antibody production following vaccination was associated with low PAX5 expression and a distinct composition of the ABC compartment. Collectively, these findings demonstrate that the characteristics of the ABC populations of older individuals are associated with antibody production following influenza vaccination.
MeSH Terms
- Adult
- Aged
- Aged, 80 and over
- Aging
- Antibodies, Viral
- Antibody Formation
- B-Lymphocytes
- Cell Proliferation
- Cells, Cultured
- Cohort Studies
- Female
- Humans
- Immunologic Memory
- Influenza A virus
- Influenza Vaccines
- Influenza, Human
- Lymphocyte Activation
- Male
- Middle Aged
- PAX5 Transcription Factor
- Vaccination
- Young Adult
During primary HIV infection (PHI), there is a striking cascade response of inflammatory cytokines and many cells of the immune system show altered frequencies and signs of extensive activation. These changes have been shown to have a relevant role in predicting disease progression; however, the challenges of identifying PHI have resulted in a lack of critical information about the dynamics of early pathogenic events. We studied soluble inflammatory biomarkers and changes in T-cell subsets in individuals at PHI ([i]n[/i] = 40), chronic HIV infection (CHI, [i]n[/i] = 56), and HIV-uninfected ([i]n[/i] = 58) recruited at the Manhiça District Hospital in Mozambique. Plasma levels of 49 biomarkers were determined by Luminex and ELISA. T-cell immunophenotyping was performed by multicolor flow cytometry. Plasma HIV viremia, CD4, and CD8 T cell counts underwent rapid stabilization after PHI. However, several immunological parameters, including Th1-Th17 CD4 T cells and activation or exhaustion of CD8 T cells continued decreasing until more than 9 months postinfection. Importantly, no sign of immunosenescence was observed over the first year of HIV infection. Levels of IP-10, MCP-1, BAFF, sCD14, tumor necrosis factor receptor-2, and TRAIL were significantly overexpressed at the first month of infection and underwent a prompt decrease in the subsequent months while, MIG and CD27 levels began to increase 1 month after infection and remained overexpressed for almost 1 year postinfection. Early levels of soluble biomarkers were significantly associated with subsequently exhausted CD4 T-cells or with CD8 T-cell activation. Despite rapid immune control of virus replication, the stabilization of the T-cell subsets occurs months after viremia and CD4 count plateau, suggesting persistent immune dysfunction and highlighting the potential benefit of early treatment initiation that could limit immunological damage.
Keywords
- AIDS
- HIV pathogenesis
- T-cell activation
- T-cell exhaustion
- acute HIV infection
- cytokines
- immunosenescence
- sub-Saharan Africa
Natural killer (NK) cells are cytotoxic innate lymphocytes that are integral to host defenses against viruses and neoplastic cells. Aging causes phenotypic and functional impairment of NK cells, which diminishes innate immune surveillance, yet the factors that determine the aged NK cell phenotype have not been completely defined. For instance, the genetic basis of the aged NK cell phenotype has not been established, but if determined, could highlight important genetic regulators of NK cells later in life. In this study, we estimated the heritability of splenic NK cell frequencies in aged mice from 15 classical and four wild-derived inbred strains. Our data suggest that frequencies of total (NKp46 CD3 ) NK and mature (NKp46 CD3 CD11b CD27 ) NK cells were highly heritable at old age, and that total NK cell frequencies were independent predictors of median strain life spans. Strains with divergent phenotypes were compared to young-adult controls, and trends of age-related NK cell phenotypic alterations were confirmed. Finally, in silico mapping techniques revealed candidate genes associated with the aged NK cell phenotype. To our knowledge, these results are the first to demonstrate the genetic basis of the aged NK cell phenotype and will inform future mechanistic studies of NK cell dysfunction during aging.
MeSH Terms
- Aging
- Animals
- Female
- Gene Expression Regulation
- Genome-Wide Association Study
- Killer Cells, Natural
- Mice
- Phenotype
- Spleen
Keywords
- Genetics
- Longevity
- Natural killer 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
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
Cellular senescence is accompanied by a senescence-associated secretory phenotype (SASP). We show here that primary human senescent CD8 T cells also display a SASP comprising chemokines, cytokines and extracellular matrix remodelling proteases that are unique to this subset and contribute to age-associated inflammation. We found the CD8 CD45RA CD27 EMRA subset to be the most heterogeneous, with a population aligning with the naïve T cells and another with a closer association to the effector memory subset. However, despite the differing processes that give rise to these senescent CD8 T cells once generated, they both adopt a unique secretory profile with no commonality to any other subset, aligning more closely with senescence than quiescence. Furthermore, we also show that the SASP observed in senescent CD8 T cells is governed by p38 MAPK signalling.
MeSH Terms
- Adult
- CD8-Positive T-Lymphocytes
- Cellular Senescence
- Cytokines
- DNA Damage
- Healthy Volunteers
- Humans
- MAP Kinase Signaling System
- Middle Aged
- Phenotype
- p38 Mitogen-Activated Protein Kinases
Keywords
SASP
- T cell
- aging
- cytokine
- inflammation
- microarray
The mechanisms involved in sequential immunoglobulin G (IgG) class switching are still largely unknown. Sequential IG class switching is linked to higher levels of somatic hypermutation (SHM) in vivo, but it remains unclear if these are generated temporally during an immune response or upon activation in a secondary response. We here aimed to uncouple these processes and to distinguish memory B cells from primary and secondary immune responses. SHM levels and IgG subclasses were studied with 454 pyrosequencing on blood mononuclear cells from young children and adults as models for primary and secondary immunological memory. Additional sequencing and detailed immunophenotyping with IgG subclass-specific antibodies was performed on purified IgG memory B-cell subsets. In both children and adults, SHM levels were higher in transcripts involving more downstream-located IGHG genes (esp. IGHG2 and IGHG4). In adults, SHM levels were significantly higher than in children, and downstream IGHG genes were more frequently utilized. This was associated with increased frequencies of CD27 IgG memory B cells, which contained higher levels of SHM, more IGHG2 usage, and higher expression levels of activation markers than CD27 IgG memory B cells. We conclude that secondary immunological memory accumulates with age and these memory B cells express CD27, high levels of activation markers, and carry high SHM levels and frequent usage of IGHG2. These new insights contribute to our understanding of sequential IgG subclass switching and show a potential relevance of using serum IgG2 levels or numbers of IgG2-expressing B cells as markers for efficient generation of memory responses.
MeSH Terms
- Adult
- Aging
- B-Lymphocytes
- Cells, Cultured
- Child
- Humans
- Immunoglobulin Class Switching
- Immunoglobulin G
- Immunologic Memory
- Immunophenotyping
- Leukocytes, Mononuclear
- Lymphocyte Activation
- Phenotype
- Somatic Hypermutation, Immunoglobulin
- Tumor Necrosis Factor Receptor Superfamily, Member 7
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
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
Immune senescence is a natural consequence of aging and may contribute to frailty and loss of homeostasis in later life. Calorie restriction increases healthy life-span in C57BL/6J (but not DBA/2J) mice, but whether this is related to preservation of immune function, and how it interacts with aging, is unclear. We compared phenotypic and functional characteristics of natural killer (NK) cells and T cells, across the lifespan, of calorie-restricted (CR) and control C57BL/6 and DBA/2 mice. Calorie restriction preserves a naïve T cell phenotype and an immature NK cell phenotype as mice age. The splenic T cell populations of CR mice had higher proportions of CD11a CD44 cells, lower expression of TRAIL, KLRG1, and CXCR3, and higher expression of CD127, compared to control mice. Similarly, splenic NK cells from CR mice had higher proportions of less differentiated CD11b CD27 cells and correspondingly lower proportions of highly differentiated CD11b CD27 NK cells. Within each of these subsets, cells from CR mice had higher expression of CD127, CD25, TRAIL, NKG2A/C/E, and CXCR3 and lower expression of KLRG1 and Ly49 receptors compared to controls. The effects of calorie restriction on lymphoid cell populations in lung, liver, and lymph nodes were identical to those seen in the spleen, indicating that this is a system-wide effect. The impact of calorie restriction on NK cell and T cell maturation is much more profound than the effect of aging and, indeed, calorie restriction attenuates these age-associated changes. Importantly, the effects of calorie restriction on lymphocyte maturation were more marked in C57BL/6 than in DBA/2J mice indicating that delayed lymphocyte maturation correlates with extended lifespan. These findings have implications for understanding the interaction between nutritional status, immunity, and healthy lifespan in aging populations.
Keywords
- T cell
- aging
- calorie restriction
- differentiation
- maturation
- natural killer cell
Common variable immunodeficiency (CVID) is a heterogeneous group of diseases. Our aim was to define sub-groups of CVID patients with similar phenotypes and clinical characteristics. Using eight-color flow cytometry, we analyzed both B- and T-cell phenotypes in a cohort of 88 CVID patients and 48 healthy donors. A hierarchical clustering of probability binning "bins" yielded a separate cluster of 22 CVID patients with an abnormal phenotype. We showed coordinated proportional changes in naïve CD4 T-cells (decreased), intermediate CD27- CD28 CD4 T-cells (increased) and CD21low B-cells (increased) that were stable for over three years. Moreover, the lymphocytes' immunophenotype in this patient cluster exhibited features of profound immunosenescence and chronic activation. Thrombocytopenia was only found in this cluster (36% of cases, manifested as Immune Thrombocytopenia (ITP) or Evans syndrome). Clinical complications more frequently found in these patients include lung fibrosis (in 59% of cases) and bronchiectasis (55%). The degree of severity of these symptoms corresponded to more deviation from normal levels with respect to CD21low B-cells, naïve CD4 and CD27− CD28 CD4 T-cells. Next-generation sequencing did not reveal any common genetic background. We delineate a subgroup of CVID patients with activated and immunosenescent immunophenotype of lymphocytes and distinct set of clinical complications without common genetic background.
MeSH Terms
- Adolescent
- Adult
- Aged
- B-Lymphocytes
- CD4-Positive T-Lymphocytes
- Cell Separation
- Cohort Studies
- Common Variable Immunodeficiency
- Female
- Fibrosis
- Flow Cytometry
- Humans
- Immunosenescence
- Lung
- Lymphocyte Activation
- Male
- Middle Aged
- Phenotype
- Purpura, Thrombocytopenic, Idiopathic
- Young Adult
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
Immune aging occurs in the elderly and in autoimmune diseases. Recently, IgD CD27 (double negative, DN) and CD21 CD11c (CD21 ) B cells were described as age-associated B cells with proinflammatory characteristics. This study investigated the prevalence and functional characteristics of DN and CD21 B cells in multiple sclerosis (MS) patients. Using flow cytometry, we demonstrated a higher proportion of MS patients younger than 60 y with peripheral expansions of DN (8/41) and CD21 (9/41) B cells compared with age-matched healthy donors (1/33 and 2/33, respectively), which indicates an increase in age-associated B cells in MS patients. The majority of DN B cells had an IgG memory phenotype, whereas CD21 B cells consisted of a mixed population of CD27 naive, CD27 memory, IgG , and IgM cells. DN B cells showed similar (MS patients) or increased (healthy donors) MHC-II expression as class-switched memory B cells and intermediate costimulatory molecule expression between naive and class-switched memory B cells, indicating their potential to induce (proinflammatory) T cell responses. Further, DN B cells produced proinflammatory and cytotoxic cytokines following ex vivo stimulation. Increased frequencies of DN and CD21 B cells were found in the cerebrospinal fluid of MS patients compared with paired peripheral blood. In conclusion, a proportion of MS patients showed increased peripheral expansions of age-associated B cells. DN and CD21 B cell frequencies were further increased in MS cerebrospinal fluid. These cells could contribute to inflammation by induction of T cell responses and the production of proinflammatory cytokines.
MeSH Terms
- Adult
- Aged
- Aging
- B-Lymphocyte Subsets
- B-Lymphocytes
- Cell Proliferation
- Cells, Cultured
- Cytotoxicity, Immunologic
- Female
- Humans
- Immunoglobulin D
- Immunologic Memory
- Inflammation Mediators
- Lymphocyte Activation
- Male
- Middle Aged
- Multiple Sclerosis
- Receptors, Complement 3d
- T-Lymphocytes
- Tumor Necrosis Factor Receptor Superfamily, Member 7
Whereas innate immune cells, such as NK and innate lymphoid cells (ILCs), have been characterized in different human tissues, knowledge on the thymic CD56-expressing cell subsets is limited. In this study, the rare subpopulations of thymic CD56 CD3 cells from samples of >100 patients have been successfully analyzed. The results revealed fundamental differences between thymic and peripheral blood (PB) CD56 CD3 cells. Thymic tissues lacked immunoregulatory CD56 CD16 NK cells but showed two Eomes CD56 subsets on which common NK cell markers were significantly altered. CD56 CD16 cells expressed high amounts of NKG2A, NKG2D, and CD27 with low CD57. Conversely, CD56 CD16 cells displayed high CD127 but low expression of KIR, NKG2D, and natural cytotoxicity receptors (NCRs). Thymic CD56 CD3 cells were able to gain cytotoxicity but were especially immunoregulatory cells, producing a broad range of cytokines. Finally, one population of thymic CD56 cells resembled conventional NK cells, whereas the other represented a novel, noncanonical NK subset.
MeSH Terms
- Adult
- Aging
- Antigens, CD
- CD56 Antigen
- Cell Degranulation
- Cell Separation
- Child
- Cytokines
- Cytotoxicity, Immunologic
- Flow Cytometry
- Humans
- Immunophenotyping
- Killer Cells, Natural
- Lymphocyte Subsets
- Microscopy, Confocal
- Microscopy, Fluorescence
- Receptors, Natural Killer Cell
- Thymus Gland
Keywords
- Eomes
- ILC
- NK cell
- NKp46
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
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
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
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
The CD27( ) IgD( ) B cell population, known as IgM memory, reduces with age. It is thought that this population is responsible for pneumococcal polysaccharide T-independent responses, and that the age-related reduction might be partially responsible for the increased susceptibility of older people to bacterial pathogens. There are other IgM( ) B cell populations that do not express IgD. We compared the different IgM populations using high-throughput sequencing of the immunoglobulin (Ig) gene repertoire and multidimensional cell phenotyping and found that the different populations of IgM cells, defined by CD27 and IgD expression, have repertoire differences. Some of these differences are likely indicative of different selection pressures in an immune response, although the older individuals were found to have a changed repertoire in naive B cells, which may contribute to some of the changes seen in memory cells. In addition, even within the CD27( ) IgD( ) IgM memory population there are multiple cell types. We show that the level of IgM expression varies substantially and hypothesize that this distinguishes between T-dependent and T-independent types of IgM memory cells. Significant age-related changes in the relative proportions of these populations may exacerbate the reduction in T-independent responders in old age.
MeSH Terms
- Adult
- Aged
- Aged, 80 and over
- Aging
- B-Lymphocyte Subsets
- Female
- Humans
- Immunoglobulin M
- Immunologic Memory
- Leukocytes, Mononuclear
- Male
- Middle Aged
- Young Adult
Keywords
- IgM memory
- aging
- immunoglobulin repertoire
Antigen-specific multifunctional T cells that secrete interferon-γ, interleukin-2 and tumour necrosis factor-α simultaneously after activation are important for the control of many infections. It is unclear if these CD8( ) T cells are at an early or late stage of differentiation and whether telomere erosion restricts their replicative capacity. We developed a multi-parameter flow cytometric method for investigating the relationship between differentiation (CD45RA and CD27 surface phenotype), function (cytokine production) and replicative capacity (telomere length) in individual cytomegalovirus (CMV) antigen-specific CD8( ) T cells. This involves surface and intracellular cell staining coupled to fluorescence in situ hybridization to detect telomeres (flow-FISH). The end-stage/senescent CD8( ) CD45RA( ) CD27(-) T-cell subset increases significantly during ageing and this is exaggerated in CMV immune-responsive subjects. However, these end-stage cells do not have the shortest telomeres, implicating additional non-telomere-related mechanisms in inducing their senescence. The telomere lengths in total and CMV (NLV)-specific CD8( ) T cells in all four subsets defined by CD45RA and CD27 expression were significantly shorter in old compared with young individuals in both a Caucasian and an Asian cohort. Following stimulation by anti-CD3 or NLV peptide, similar proportions of triple-cytokine-producing cells are found in CD8( ) T cells at all stages of differentiation in both age groups. Furthermore, these multi-functional cells had intermediate telomere lengths compared with cells producing only one or two cytokines after activation. Therefore, global and CMV (NLV)-specific CD8( ) T cells that secrete interferon-γ, interleukin-2 and tumour necrosis factor-α are at an intermediate stage of differentiation and are not restricted by excessive telomere erosion.
MeSH Terms
- Adult
- Age Factors
- Aged
- Aged, 80 and over
- Aging
- Asian Continental Ancestry Group
- Biomarkers
- CD8-Positive T-Lymphocytes
- Cell Differentiation
- Cell Proliferation
- Cells, Cultured
- Cellular Senescence
- Cytokines
- Cytomegalovirus
- Cytomegalovirus Infections
- European Continental Ancestry Group
- Flow Cytometry
- Humans
- Immunophenotyping
- Leukocyte Common Antigens
- London
- Lymphocyte Activation
- Phenotype
- Singapore
- Telomere
- Telomere Shortening
- Tumor Necrosis Factor Receptor Superfamily, Member 7
- Young Adult
Keywords
- CD8 T cells
- cytomegalovirus
- multi-functional
- senescence
- telomere
Memory B cells (MBCs) have a very long life-span as compared to naïve B cells (NBCs), remaining viable for years. It could predispose them to suffer misbalances in the gene expression pattern at the long term, which might be involved in the development of age-related B-cell disorders. In order to identify genes whose expression might change during life, we analyzed the gene expression patterns of CD27 NBCs versus CD27 MBCs in young and old subjects. Using microarray assays we observed that the expression pattern of CD27 NBCs versus CD27 MBCs is significantly different. Furthermore, in order to evaluate the age effect, we compared the gene expression pattern of young versus aged subjects in both cell populations. Interestingly, we did not find significant differences in the CD27 NBC population between young and aged individuals, whereas we found 925 genes differentially expressed in CD27 MBCs. Among these genes, 193 were also differentially expressed in CD27 MBCs as compared to CD27 NBCs, most of them involved in cell survival, cell growth and proliferation, cellular development and gene expression. We conclude that gene expression profiles of CD27 NBCs and CD27 MBCs are different. Moreover, whereas the gene expression pattern of CD27 MBCs varies with age, the same does not happen in CD27 NBCs. This suggests that MBCs undergo time-dependent changes which could underlie a higher susceptibility to dysfunction with age. This article is protected by copyright. All rights reserved.
Keywords
- B-cell disorders
- cell survival
- longevity
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
Immunosenescence is characterized by the impairment of humoral immunity with changes in the memory/naive B cell compartment. In particular we have previously reported the percentage increase of a Memory IgD(-)CD27(-) (Double Negative, DN) B cell population in aged people. In this study, we have further characterized DN B cells with the aim to better understand their contribution to immunosenescence. As DN B cells show a poor ability to proliferate in vitro, we have evaluated the expression of the inhibitory receptors CD307d and CD22 on these cells from young and old individuals. In addition we have evaluated the ability to activate DN B cells by the simultaneous use of innate (CpG) and adaptive (α-Ig/CD40) ligands. Our data demonstrate that the refractoriness to proliferate of DN B cells does not depend on the expression of inhibitory receptors, but it is due to the kind of stimulation. Indeed, when DN B cells are stimulated engaging both BCR and TLR9, they become able to proliferate and reactivate the telomerase enzyme. In the present study, we have also compared the telomerase activity in a group of people genetically advantaged for longevity as centenarian offspring (CO) and in a group of moderate-severe Alzheimer's disease (AD) patients, who represent a model of unsuccessful aging. Our study suggests that telomerase reactivation of DN B cells, as well as their number and ability in activating, depend essentially by the biological age of the subjects studied, so the evaluation of DN B cells might allow to gain insight to healthy and unsuccessful aging.
MeSH Terms
- Adult
- Age Factors
- Aged
- Aged, 80 and over
- Alzheimer Disease
- Antigens, Surface
- B-Lymphocyte Subsets
- Cellular Senescence
- Humans
- Immunologic Memory
- Immunophenotyping
- Lymphocyte Activation
- Middle Aged
- Phenotype
- Receptors, Antigen, B-Cell
- Severity of Illness Index
- Telomerase
- Young Adult
Keywords
- Aging
- Alzheimer
- B lymphocytes
- Centenarian offspring
- Inflammation
- Telomerase
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
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