KLRG1
Killer cell lectin-like receptor subfamily G member 1 (C-type lectin domain family 15 member A) (ITIM-containing receptor MAFA-L) (MAFA-like receptor) (Mast cell function-associated antigen) [CLEC15A] [MAFA] [MAFAL]
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With the challenges that aging populations pose to healthcare, interventions that facilitate alleviation of age-related morbidities are imperative. A prominent risk factor for developing age-related morbidities is immunosenescence, characterized by increased chronic low-grade inflammation, resulting in T-cell exhaustion and senescence. Contact with nature and associated physical activities have been shown to boost immunity in older adults and may be promoted in the form of Horticultural Therapy (HT). We aimed to examine the effects of HT on immunosenescence. We conducted a randomized controlled trial with 59 older adults assigned to either the HT intervention or waitlist control group. Older adults in the HT intervention group underwent HT intervention program over six months. Venous blood was drawn at baseline and at the 3 rd and 6 th month from the commencement of this study. For participants who attended all three blood collection time points (HT: n=22, waitlist: n=24), flow cytometry analysis was performed on whole blood samples to evaluate the kinetics of lymphocyte subsets over the intervention period, revealing the composition of CD4 and CD8 subsets expressing exhaustion markers - CD57, CTLA4, and KLRG1. Enzyme-linked immunosorbent assays were employed to measure changes in plasma IL-6 levels. HT is associated with increased numbers of naïve CD8 T cells and fewer CTLA4-expressing terminally differentiated effector CD4 and CD8 memory T cells re-expressing CD45RA (TEMRA). Furthermore, IL-6 levels were reduced during HT, and the frequencies of naive and TEMRA CD8 T cells were found to be associated with IL-6 levels. HT is associated with a reduction in the levels of biomarkers that measure the extent of T-cell exhaustion and inflammaging in older adults. The positive effects of HT on T-cell exhaustionwere associated with the reduction of IL-6 levels.
Keywords
- CTLA-4
- Geroscience
- IL-6
- Immunosenescence
- Inflammaging
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
Cognitive impairment is common in systemic lupus erythematosus (SLE) patients with substantial adverse effects on function and quality of life. One hypothesis to understand the mechanisms of cognitive impairment in SLE is accelerated immunosenescence. The aim of this study is to observe the correlation between immunosenescence with cognitive impairment in patients with SLE. Sixty-one female SLE patient were measured for CD4 and CD8 T cell-associated senescence markers, including percentage of end-stage differentiated T cells (CD4 and CD8 T cells expressing CD57 or loss of CD28 expression), of naïve T cells (CD4 CD45RA and CD8 CD45RA ), memory T cells (CD4 CD45RO and CD8 CD45RO ), and antigen-experienced T cells (CD4 KLRG1 and CD8 KLRG1 ) which were measured using flow cytometry. One hallmark of immunosenescence called immune risk profile (IRP) was defined by an inverted ratio of CD4 and CD8. Cognitive functions were measured by Mini-Mental State Examination (MMSE) and Montréal Cognitive Assessment (MOCA) questionnaire. Thirty-six (59.1%) SLE patients who had IRP develop significantly lower attention and recall from both MMSE (P = .005 and P = .000) and MOCA (P = .017 and P = .000) examinations. Decreased visuospatial ability was also found in patients with IRP measured by MOCA (P = .046). There was a negative correlation between memory CD4 CD45RO T cells with recall and visuospatial domain (R = -0.204, P = .039 and R = -0.250, P = .033; respectively), and negative correlation between CD8 CD28 T cells with recall and attention domain (R = -0.249, P = .027 and R = -0.145, P = .048, respectively). Systemic lupus erythematosus patients develop an accelerated immunosenescence which contributes to cognitive dysfunction, especially in attention, recall, and visuospatial domains.
Keywords
- immunosenescence
- lupus-associated brain fog
- systemic lupus erythematosus
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
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
Older kidney transplant recipients experience increased rates of infection and death, and less rejection, compared with younger patients. However, little is known about immune dysfunction in older compared with younger kidney transplant recipients and whether it is associated with infection. We evaluated T cell phenotypes including maturation, immune senescence, and exhaustion in a novel investigation into differences in older compared with younger patients receiving identical immune suppression regimens. We evaluated PBMC from 60 kidney transplant recipients (23 older and 37 matched younger patients) by multiparameter immune phenotyping. Older kidney transplant recipients demonstrated decreased frequency of naïve CD4 and CD8 T cells, and increased frequency of terminally differentiated, immune senescent, and NK T cells expressing KLRG1. There was a trend towards increased frequency of T cell immune senescence in patients experiencing infection in the first year after transplantation, which reached statistical significance in a multivariate analysis. This pilot study reveals immune dysfunction in older compared with younger transplant recipients, and suggests a likely mechanism for increased vulnerability to infection. The ability to assess T cell maturation and immune senescence in transplant recipients offers the potential for risk stratification and customization of immune suppression to prevent infection and rejection after transplantation.
MeSH Terms
- Adult
- Age Factors
- Aged
- Aged, 80 and over
- Cell Differentiation
- Cellular Senescence
- Female
- Graft Rejection
- Humans
- Immunocompromised Host
- Kidney Transplantation
- Lymphocyte Subsets
- Male
- Middle Aged
- Natural Killer T-Cells
- Phenotype
- T-Lymphocytes
- Young Adult
Keywords
- Elderly
- Immunosenescence
- Infection
- Kidney transplantation
- T cell
Immune-aging is associated with perturbed immune responses in the elderly. CD161-expressing T cells, i.e., the previously described subsets of CD161 CD4 T cells, CD161 CD8 T cells, and CD161 CD8 T cells, are highly functional, pro-inflammatory T cells. These CD161-expressing T cells are critical in immunity against microbes, while possibly contributing to autoimmune diseases. So far, little is known about the impact of aging on the frequency, phenotype, and function of these CD161-expressing T cells. In the current study, we investigated the impact of aging on CD161 CD4 T cells, CD161 CD8 T cells, and CD161 CD8 T cells in peripheral blood samples of 96 healthy subjects (age 20-84). Frequencies of CD161 CD4 T cells and CD161 CD8 T cells were stable with aging, whereas frequencies of CD161 CD8 T cells declined. Although CD161 CD8 T cells were mostly T cell receptor-Vα7.2 mucosal-associated invariant T cells, CD161 expressing CD4 and CD8 T cells showed a limited expression of markers for gamma-delta T cells or invariant natural killer (NK) T cells, in both young and old subjects. In essence, CD161-expressing T cells showed a similar memory phenotype in young and old subjects. The expression of the inhibitory NK receptor KLRG1 was decreased on CD161 CD4 T cells of old subjects, whereas the expression of other NK receptors by CD161-expressing T cells was unaltered with age. The expression of cytotoxic effector molecules was similar in CD161 and CD161 CD8 T cells of young and old subjects. The ability to produce pro-inflammatory cytokines was preserved in CD161 and CD161 CD8 T cells of old subjects. However, the percentages of IFN-γ and interleukin-17 cells were significantly lower in CD161 CD4 T cells of old individuals than those of young individuals. In addition, aging was associated with a decrease of nonclassic T helper 1 cells, as indicated by decreased percentages of CD161-expressing cells within the IFN-γ CD4 T cell compartment of old subjects. Taken together, aging is associated with a numerical decline of circulating CD161 CD8 T cells, as well as a decreased production of pro-inflammatory cytokines by CD161 CD4 T cells. These aging-associated changes could contribute to perturbed immunity in the elderly.
MeSH Terms
- Adult
- Aged
- Aged, 80 and over
- Aging
- Female
- Humans
- Male
- Middle Aged
- NK Cell Lectin-Like Receptor Subfamily B
- Phenotype
- T-Lymphocytes
- Young Adult
Keywords
- CD161
- T helper 1 cells
- T helper 17 cells
- T lymphocytes subsets
- aging
- cytokines
- mucosal-associated invariant T cell
The purpose of this study was to quantify and characterize peripheral blood regulatory T cells (Tregs), as well as the IL-10 plasma concentration, in Masters athletes at rest and after an acute exhaustive exercise test. Eighteen Masters athletes (self-reported training: 24.6 ± 1.83 years; 10.27 ± 0.24 months and 5.45 ± 0.42 h/week per each month trained) and an age-matched control group of ten subjects (that never took part in regular physical training) volunteered for this study. All subjects performed an incremental test to exhaustion on a cycle ergometer. Blood samples were obtained before (Pre), 10 min into recovery (Post), and 1 h after the test (1 h). Absolute numbers of Tregs were similar in both groups at rest. Acute exercise induced a significant increase in absolute numbers of Tregs at Post (0.049 ± 0.021 to 0.056 ± 0.024 × 10 /L, P = 0.029 for Masters; 0.048 ± 0.017 to 0.058 ± 0.020 × 10 /L, P = 0.037 for control) in both groups. Treg mRNA expression for FoxP3, IL-10, and TGF-β in sorted Tregs was similar throughout the trials in both groups. Masters athletes showed a higher percentage of subjects expressing the FoxP3 (100% for Masters vs. 78% for Controls, P = 0.038) and TGF-β (89% for Masters vs. 56% for Controls, P = 0.002) after exercise and a higher plasma IL-10 concentration (15.390 ± 7.032 for Masters vs. 2.411 ± 1.117 for control P = 0.001, ES = 2.57) at all timepoints. KLRG1 expression in Tregs was unchanged. Our findings showed that Masters athletes have elevated anti-inflammatory markers and maintain the number of Tregs, and may be an adaptive response to lifelong training.
MeSH Terms
- Adaptation, Physiological
- Adult
- Athletes
- Exercise
- Female
- Forkhead Transcription Factors
- Humans
- Interleukin-10
- Lectins, C-Type
- Male
- Receptors, Immunologic
- T-Lymphocytes, Regulatory
- Trans-Activators
- Transforming Growth Factor beta
Keywords
- Aging
- FoxP3
- Interleukin-10
- Master athletes
- TGF-beta
- Treg cells
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
Killer cell lectin-like receptor subfamily G member 1 (KLRG1) has been found on human memory T lymphocytes. However, the roles of KLRG1 on human T cells especially in tumor microenvironment have not been fully understood. Our results showed KLRG1 expression on T cells significantly increased in tumor microenvironment. KLRG1 T cells exhibited poor proliferative capacity with decreased effector cytokine production. Meanwhile, KLRG1 T cells expressed abundant pro-inflammatory cytokines and demonstrated high level of Foxp3 expression. KLRG1 T cells showed decreased expression of miRNA-101 and higher expression of CtBP2. Our results indicated KLRG1 might contribute to the impaired antitumor immunity of memory T cells in tumor microenvironment. Thus, repressing KLRG1 on human memory T cells might be a novel therapeutics against cancer.
MeSH Terms
- Alcohol Oxidoreductases
- Cell Line, Tumor
- Cell Proliferation
- Cell Separation
- Cellular Senescence
- Co-Repressor Proteins
- Cytokines
- Flow Cytometry
- Forkhead Transcription Factors
- Humans
- Immunologic Memory
- Immunophenotyping
- Killer Cells, Natural
- Lectins, C-Type
- Leukocytes, Mononuclear
- MicroRNAs
- Neoplasms
- Nerve Tissue Proteins
- Receptors, Immunologic
- Signal Transduction
- T-Lymphocyte Subsets
- Trans-Activators
- Tumor Microenvironment
Keywords
- KLRG1
- antitumor immunity
- memory T cells
- senescence
Psychosocial stress is thought to play a key role in the acceleration of immunological aging. This study investigated the relationship between lifetime and past-year history of post-traumatic stress disorder (PTSD) and the distribution of T cell phenotypes thought to be characteristic of immunological aging. Data were from 85 individuals who participated in the community-based Detroit Neighborhood Health Study. Immune markers assessed included the CD4:CD8 ratio, the ratio of late-differentiated effector (CCR7-CD45RA CD27-CD28-) to naïve (CCR7 CD45RA CD27 CD28 ) T cells, the percentage of KLRG1-expressing cells, and the percentage of CD57-expressing cells. In models adjusted for age, gender, race/ethnicity, education, smoking status, and medication use, we found that past-year PTSD was associated with statistically significant differences in the CD8 T cell population, including a higher ratio of late-differentiated effector to naïve T cells, a higher percentage of KLRG1 cells, and a higher percentage of CD57 cells. The percentage of CD57 cells in the CD4 subset was also significantly higher and the CD4:CD8 ratio significantly lower among individuals who had experienced past-year PTSD. Lifetime PTSD was also associated with differences in several parameters of immune aging. PTSD is associated with an aged immune phenotype and should be evaluated as a potential catalyzer of accelerated immunological aging in future studies.
MeSH Terms
- Adult
- Aged
- Aged, 80 and over
- Cellular Senescence
- Female
- Humans
- Immunophenotyping
- Male
- Middle Aged
- Phenotype
- Stress Disorders, Post-Traumatic
- T-Lymphocyte Subsets
- Young Adult
Keywords
- Aging
- Detroit
- Immunity
- Immunosenescence
- Post traumatic stress disorder
- T cells
Despite effective antiretroviral therapy (ART), HIV-infected patients exhibit systemic inflammation, early onset of age-related diseases, and features of immunosenescence. The role of inflammation in the development of age-related diseases is widely recognized. However, the role of immunosenescence is not well established. Studying immunosenescence in HIV-infection could give insight into its role in ageing processes. In this cross-sectional study, we aimed to investigate whether ART-treated HIV-infected patients exhibit immunosenescence; and whether immunosenescence is associated with age-related processes of inflammation, metabolism, adipose tissue, and muscle. T cell immunosenescence and exhaustion were assessed by flow cytometry analysis of CD8 ( ) cells from 43 ART-treated HIV-infected patients (HIV( )) and ten Controls using markers of differentiation: CD27/CD28; maturation: CD27/CD45RA; senescence: killer cell lectin-like receptor G1 (KLRG1); and exhaustion: programmed death-1 (PD-1). Relationships between CD8 ( ) T cell immunosenescence, exhaustion, and age-related processes were assessed using linear regressions. HIV-infection was strongly associated with more highly differentiated and mature CD8 ( ) T cell phenotypes. PD-1 and KLRG1 expression did not differ between HIV( ) and Controls, but depended on differentiation and maturation stages of the cells. CD8 ( ) T cell maturation was associated with age. KLRG1 expression was associated with age, metabolic syndrome, visceral adipose tissue, and high muscle mass. PD-1 expression was not associated with age-related parameters. HIV-infection strongly affected CD8 ( ) T cell differentiation and maturation, whereas age-related processes were only weakly associated with immune parameters. Our findings suggest that, in contrast to inflammation, immunosenescence appears to be highly dependent on HIV-infection and is only to a small extent associated with age-related parameters in well-treated HIV-infection.
MeSH Terms
- Adipose Tissue
- Age Factors
- Antiretroviral Therapy, Highly Active
- Biomarkers
- Body Composition
- CD8-Positive T-Lymphocytes
- Case-Control Studies
- Cross-Sectional Studies
- Cytokines
- Energy Metabolism
- Female
- Gene Expression
- HIV Infections
- HIV-1
- Humans
- Immunomodulation
- Immunophenotyping
- Immunosenescence
- Inflammation Mediators
- Lectins, C-Type
- Male
- Muscles
- Programmed Cell Death 1 Receptor
- Receptors, Immunologic
- T-Lymphocyte Subsets
- Trans-Activators
The redeployment of NK-cells in response to an acute bout of exercise is thought to be an integral component of the "fight-or-flight" response, preparing the body for potential injury or infection. We showed previously that CMV seropositivity impairs the redeployment of NK-cells with exercise in the young. In the current study, we examined the effect of aging on the redeployment of NK-cells with exercise in the context of CMV. We show here that CMV blunts the exercise-induced redeployment of NK-cells in both younger (23-39 yrs) and older (50-64 yrs) subjects with older CMV(neg) subjects showing the largest postexercise mobilization and 1 h postexercise egress of NK-cells. The blunted exercise response in CMV(pos) individuals was associated with a decreased relative redeployment of the CD158a and CD57 NK-cell subsets in younger and older individuals. In addition, we show that aging is associated with a CMV-independent increase in the proportion of NK-cells expressing the terminal differentiation marker CD57, while CMV is associated with an age-dependent decrease in the proportion of NK-cells expressing the inhibitory receptors KLRG1 (in the younger group) and CD158a (in the older group). Collectively, these data suggest that CMV may decrease NK-cell mediated immunosurveillance after exercise in both younger and older individuals.
MeSH Terms
- Adult
- Aging
- CD57 Antigens
- Cytomegalovirus Infections
- Exercise
- Flow Cytometry
- Humans
- Killer Cells, Natural
- Male
- Middle Aged
- Oxygen Consumption
- Phenotype
- Receptors, KIR2DL1
- Young Adult
CD8 T cells used in adoptive immunotherapy may be manipulated to optimize their effector functions, tissue-migratory properties and long-term replicative potential. We reported that antigen-stimulated CD8 T cells transduced to express an active form of the transcription factor signal transducer and activator of transcription 5 (STAT5CA) maintained these properties upon adoptive transfer. We now report on the requirements of STAT5CA-expressing CD8 T cells for cell survival and proliferation in vivo. We show that STAT5CA expression allows for greater expansion of T cells in vivo, while preserving dependency on T-cell-receptor-mediated tonic stimulation for their in vivo maintenance and return to a quiescent stage. STAT5CA expression promotes the formation of a large pool of effector memory T cells that respond upon re-exposure to antigen and present an increased sensitivity to γc receptor cytokine engagement for STAT5 phosphorylation. In addition, STAT5CA expression prolongs the survival of what would otherwise be short-lived terminally differentiated KLRG1-positive effector cells with up-regulated expression of the senescence-associated p16(INK) (4A) transcripts. However, development of a KLRG1-positive CD8 T cell population was independent of either p16(INK) (4A) or p19(ARF) expression (as shown using T cells from CDKN2A(-/-) mice) but was associated with expression of transcripts encoding p15(INK) (4B) , another protein involved in senescence induction. We conclude that T-cell-receptor- and cytokine-dependent regulation of effector T cell homeostasis, as well as mechanisms leading to senescent features of a population of CD8 T cells are maintained in STAT5CA-expressing CD8 T cells, even for cells that are genetically deficient in expression of the tumour suppressors p16(INK) (4A) and p19(ARF) .
MeSH Terms
- Animals
- CD8-Positive T-Lymphocytes
- Cell Differentiation
- Cell Proliferation
- Cellular Senescence
- Cyclin-Dependent Kinase Inhibitor p15
- Cyclin-Dependent Kinase Inhibitor p16
- Gene Expression Regulation
- Lectins, C-Type
- Mice
- Mice, Knockout
- Receptors, Antigen, T-Cell
- Receptors, Immunologic
- STAT5 Transcription Factor
Keywords
- effector CD8 T cell
- gene regulation
- immunotherapy
- senescence
- transcription factor
Coinfection of hepatitis B virus (HBV) with hepatitis C virus (HCV) is quite common, leading to an increase in morbidity and mortality. As such, HBV vaccination is recommended in HCV-infected individuals. However, HBV vaccine responses in HCV-infected individuals are often blunted compared with uninfected populations. The mechanism for this failure of vaccine response in HCV-infected subjects remains unclear. In this study, we investigated the expression and function of an inhibitory receptor, killer cell lectin-like receptor subfamily G member 1 (KLRG1), in the regulation of CD4( ) T cells and HBV vaccine responses during HCV infection. We demonstrated that KLRG1 was overexpressed on CD4( ) T cells from HCV-infected, HBV vaccine nonresponders compared with HBV vaccine responders. The capacity of CD4( ) T cells to proliferate and secrete IL-2 cytokine was inversely associated with the level of KLRG1 expression. Importantly, blocking KLRG1 signaling resulted in a significant improvement in CD4( ) T cell proliferation and IL-2 production in HCV-infected, HBV vaccine nonresponders in response to TCR stimulation. Moreover, blockade of KLRG1 increased the phosphorylation of Akt (Ser(473)) and decreased the expression of cell cycle inhibitors p16(ink4a) and p27(kip1), which subsequently enhanced the expression of cyclin-dependent kinase 2 and cyclin E. These results suggest that the KLRG1 pathway impairs CD4( ) T cell responses to neoantigen and induces a state of immune senescence in individuals with HCV infection, raising the possibility that blocking this negative-signaling pathway might improve HBV vaccine responses in the setting of chronic viral infection.
MeSH Terms
- Aging
- CD4-Positive T-Lymphocytes
- Cell Proliferation
- Cells, Cultured
- Coinfection
- Cyclin E
- Cyclin-Dependent Kinase 2
- Cyclin-Dependent Kinase Inhibitor p16
- Cyclin-Dependent Kinase Inhibitor p27
- Hepacivirus
- Hepatitis B
- Hepatitis B Vaccines
- Hepatitis B virus
- Hepatitis C
- Humans
- Interleukin-2
- Lectins, C-Type
- Phosphorylation
- Proto-Oncogene Proteins c-akt
- Receptors, Immunologic
- Signal Transduction
- Trans-Activators
Dynamic exercise evokes a rapid redeployment of cytotoxic T cell subsets with high expression of β2 adrenergic receptors, presumably to enhance immunosurveillance during acute stress. As this response is affected by age and infection history, this study examined latent CMV infection as a potential confounder to age-related differences in blood CD8 T-cell responses to exercise. Healthy young (n=16) and older (n=16) humans counterbalanced by CMV IgG serostatus (positive or negative) exercised for 30-min at ∼80% peak cycling power. Those with CMV redeployed ∼2-times more CD8 T-cells and ∼6-times more KLRG1 /CD28- and CD45RA /CCR7- CD8 subsets than non-infected exercisers. Seronegative older exercisers had an impaired redeployment of total CD8 T-cells, CD45RA /CCR7 and KLRG1-/CD28 CD8 subsets compared to young. Redeployed CD8 T-cell numbers were similar between infected young and old. CMVpp65 specific CD8 cells in HLA/A2(∗) subjects increased ∼2.7-fold after exercise, a response that was driven by the KLRG1 /CD28-/CD8 subset. Stimulating PBMCs before and after exercise with CMVpp65 and CMV IE-1 antigens and overlapping peptide pools revealed a 2.1 and 4.4-fold increases in CMVpp65 and CMV IE-1 IFN-γ secreting cells respectively. The breadth of the T cell response was maintained after exercise with the magnitude of the response being amplified across the entire epitope repertoire. To conclude, latent CMV infection overrides age-related impairments in CD8 T-cell redeployment with exercise. We also show for the first time that many T-cells redeployed with exercise are specific to CMVpp65 and CMV IE-1 antigens, have broad epitope specificity, and are mostly of a high-differentiated effector memory phenotype.
MeSH Terms
- Adult
- Age Factors
- CD8-Positive T-Lymphocytes
- Cytomegalovirus Infections
- Exercise
- Humans
- Male
- Middle Aged
- T-Lymphocyte Subsets
- Young Adult
Keywords
- Aging
- Exercise immunology
- Herpesvirus
- Immunosenescence
- Lymphocyte
- T-cells
Aged individuals have increased morbidity and mortality following influenza and other viral infections, despite previous exposure or vaccination. Mouse and human studies suggest increased senescence and/or exhaustion of influenza virus-specific CD8 T cells with advanced age. However, neither the relationship between senescence and exhaustion nor the underlying transcriptional pathways leading to decreased function of influenza virus-specific cellular immunity in elderly humans are well-defined. Here, we demonstrate that increased percentages of CD8 T cells from aged individuals express CD57 and KLRG1, along with PD-1 and other inhibitory receptors, markers of senescence, or exhaustion, respectively. Expression of T-box transcription factors, T-bet and Eomes, were also increased in CD8 T cells from aged subjects and correlated closely with expression of CD57 and KLRG1. Influenza virus-specific CD8 T cells from aged individuals exhibited decreased functionality with corresponding increases in CD57, KLRG1, and T-bet, a molecular regulator of terminal differentiation. However, in contrast to total CD8 T cells, influenza virus-specific CD8 T cells had altered expression of inhibitory receptors, including lower PD-1, in aged compared with young subjects. Thus, our data suggest a prominent role for senescence and/or terminal differentiation for influenza virus-specific CD8 T cells in elderly subjects.
MeSH Terms
- Adult
- Aged
- Aging
- CD8-Positive T-Lymphocytes
- Cellular Senescence
- Female
- Flow Cytometry
- Humans
- Influenza, Human
- Male
- T-Box Domain Proteins
- Young Adult
Keywords
- CD107
- CD57
- Eomes
- KLRG-1
- PD-1
- exhaustion