T-cell Senescence Research Articles

Latent CMV and EBV infections and the mobilization of viral-specific and senescent T-cells with exercise (102.6)

Abstract Exercise mobilizes senescent T-cells into the blood but the impact of latent CMV and EBV infections on this response is unknown. This study aimed to determine if: (1) CMV or EBV specific T-cells are mobilised in response to exercise; and (2) the impact of CMV and EBV on the exercise-responsiveness of senescent T-cells. 24 healthy males (age 28.5 ± 5) completed a 30-min cycling protocol at 85% of maximum power. PBMCs isolated before, immediately after and 1hour after exercise were labelled with MHC class I Pentamers specific to CMV (pp65) or EBV (LMP-2) and assayed for Naïve (KLRG1-/CD28+/CD57-), effector-memory (KLRG1+/CD28+/CD57-) and senescent (KLRG1+/CD28-/CD57+) surface markers. Exercise increased CMV and EBV-specific T-cell numbers by 158% and 200% respectively, and altered the proportions of senescent (+44%) and naïve (-20%) CD8+ T-cells. CMV+ had a greater (+136%) proportion of senescent and a lower (-33%) proportion of naïve CD8+ T-cells compared to CMV-, and demonstrated a greater egress of senescent T-cells in response to exercise. Senescent markers on both CMV and EBV-specific T-cells increased with exercise (+53% and +76% respectively). To conclude, CMV and EBV specific CD8+ T-cells are mobilized into blood with acute exercise and those infected with CMV demonstrate a greater relative egress of senescent T-cells during exercise recovery. Future work will determine the potential impact of exercise in altering senescent T-cell frequency in those infected with CMV

Early Aged T-Cells in Immune-Mediated Diseases

Early loss of thymic function may be crucial for the development of immune-mediated diseases. According to this concept premature collapse of thymic output is compensated by homeostatic proliferation of peripheral T-cells, driven by recognition of self antigens and finally resulting in the expansion of autoreactive, senescent T-cell clones. Such senescent T-cells are characterized by the loss of the co-stimulatory receptor CD28 and the gain of new immunomodulatory molecules such as natural killer cell receptors and toll-like receptors. The immune system may compensate for these changes by regulatory mechanisms, including the evolvement of regulatory T-cells. However, the aging process may also affect these regulatory T-cells leading to a second “hit” of the immune system. Current therapeutic approaches in patients with immune-mediated diseases target common end pathways of inflammation, driven by proinflammatory cytokines and effector cells. Future directions will include the aim to reset the immune system, by restoring the ability to repopulate the immune system with young and adaptable lymphocytes as well as by strengthening the effect of regulatory T-cells. Keywords: CD28, aging, regulatory T-lymphocyte, cellular senescence, thymus, autoimmune disease, T-Cells, natural killer cell, toll-like receptors, immune system, inflammation, cytokines, homeostasis, rheumatoid arthritis, innate immune system, thymopoesis, autoimmune regulator, juvenile idiopathic arthritis, haematopoietic progenitor cells, major histocompatibility complex M, MHC II, HLA-DR4, thymic atrophy, autoimmune diseases, Epstein Barr Virus, EBV, CD4, CD8, CD27, IFN, perforin, granzyme B, CCR-5, CCR-7, Ankylosing spondylitis, Dermatomyositis, 50

Association with inflammatory cells and apolipoproteins to the progression of atherosclerosis

PurposeInflammatory cells are known to be associated with the progression of atherosclerosis and plaque rupture. However, the relation to inflammatory cells and apolipoproteins on the progression of atherosclerosis is unknown. This study was aimed at examining the different expressions of inflammatory cells and evaluate the effect of apolipoprotein (APO) C1 and APO E during the progression of atherosclerosis.MethodsTen atherosclerotic tissues were compared with five non-atherosclerotic tissues. The presence of vascular smooth muscle cells (VSMCs), macrophages, T-cells, APO C1, and APO E were identified by Western blotting and immunohistochemical analysis with antibodies. The senescence was analyzed by senescence-associated β-galactosidase.ResultsThe protein expression and senescence of macrophages, APO C1 and APO E were significantly higher in the main atherosclerotic lesion than the non-atherosclerotic lesion. A high concentration of inflammatory cells and the paucity of VSMCs were present in the shoulder area. In addition, macrophage and T-cells are expressed in the early stage of atherosclerotic development and more expanded in advanced atherosclerotic plaques. APO C1 was expressed mainly within the necrotic core, and APO E existed mostly around the necrotic core and the fibrous cap in advanced atherosclerotic plaques.ConclusionOur study indicated that the expression and the senescence of macrophage and T-cells may be closelyrelated to induction and deposition of APO C1 and APO E. This contributes to the development and progression of atherosclerotic plaque by expanding the necrotic core.

Skewed T-cell maturation and function in HIV-infected patients failing CD4+ recovery upon long-term virologically suppressive HAART

Analysis of functionally defined T-cell differentiation in HIV-infected patients with low CD4(+) on virologically suppressive HAART is crucial to design clinically efficacious treatments. We cross-sectionally investigated the maturation (CD45RA/CCR7, CD7) and function [antigen-specific enzyme-linked immunosorbent spot assay (ELISPOT), interleukin-2 (IL-2)/interferon-gamma-producing cells] of CD4(+) and CD8(+) T cells in 34 HIV-infected immunological nonresponders (INRs): CD4(+) cell count less than or equal to 200 cells/microl, HIV-RNA 50 copies/ml or less, as compared to 20 full responders (CD4(+) > 500 cells/microl, HIV-RNA < 50 copies/ml). We describe skewed T-cell maturation in INRs with outgrowth of effector memory CD45RA(-)CCR7(-) CD4(+)/CD8(+) and Th2-committed CD7(-)CD4(+), and reduced unprimed-naive T cells (P = 0.001). Functionally, INRs display reduced Gag-specific ELISPOT (P = 0.04) and IL-2-secreting CD8(+) (P = 0.08) while showing CMV-specific responses comparable to full responders. CD4 lymphopenia on HAART results in skewed, senescent T-cell maturation profile, inefficient T-helper function and poor HIV-specific CD8(+) response. This delineates a functional/phenotypic T-cell pattern that correlates to unfavourable clinical outcome.

Changes In The Frequency Of Senescent Blood T-cells During 6-months Training Preparation For An Ironman Triathlon

It is well-known that athletes are at an increased susceptibility to illness when adhering to arduous training regimens in preparation for endurance events. Senescent T-lymphocytes are antigen-experienced cells that accumulate with age and fail to clonally expand following further antigenic stimulation, thus predisposing the individual to a greater risk of infection. Although acute exercise is known to alter the frequency of senescent T-cells in blood, less is known about the effects of long-term endurance training. PURPOSE: To examine the effects of 6-months training preparation for an Ironman triathlon on the frequency of senescent blood T-cells. METHODS: Ten club-level triathletes (9 males; 1 female: Age: 42.9 ± 3.1 yrs) provided a fasted resting blood sample in the morning at 27 (DEC), 21 (JAN), 15 (MAR), 9 (MAY) and 3 (JUN) weeks before the 2008 Zurich Ironman Triathlon. An additional sample was collected 2-weeks post-competition (AUG). Total training hours completed by the participants over the 6-month period was 284.4 ± 122.9. Isolated blood lymphocytes were labelled with monoclonal antibodies to assess cell surface expression and co-expression of the T-cell senescence markers KLRG1, CD57 and CD28; and the naïve and memory T-cell markers CD45RA and CD45RO on CD3+, CD3+/CD4+ and CD3+/CD8+ T-cells using four-colour flow cytometry. Data was analyzed for time-change using a repeated measures linear mixed model. RESULTS: Compared to DEC, the percentage of CD4+ T-cells expressing KLRG1 increased by 71% (MAR), 20% (MAY) and 71% (AUG). CD4+ T-cells co-expressing KLRG1 and CD57 was 192% greater in AUG compared to DEC. No changes in senescent markers were found on CD8+ T-cells. The proportion of transitional T-cells (CD45RA+/CD45RO+) increased from MAY to JUN by 141% and 115% for CD4+ and CD8+ T-cells respectively. The proportion of memory CD8+ T-cells (CD45RA-/CD45RO+) was 40% (MAY) and 55% (AUG) greater than DEC. CONCLUSION: Adherence to a 6-month training program in preparation for an Ironman triathlon leads to an increased frequency of senescent CD4+ T-cells (KLRG1+/CD57+) and a greater proportion of naïve to memory transitional CD4+ and CD8+ T-cells in blood. These changes could have important implications for athlete infection risk during periods of arduous training.

A Greater Vo2max Is Associated With A Reduced Frequency Of Senescent Blood T-cells In Middle-aged But Not Younger Men

The clonal expansion of T-lymphocytes in response to an antigenic stimulus is an essential process of adaptive immunity. Chromosome telomeres become progressively eroded with each round of cell division, eventually leading to replicative senescence. T-lymphocytes with a senescent phenotype are known to accumulate with age, increasing infection risk in middle-aged and elderly individuals. A sedentary lifestyle is associated with shortened telomeres in peripheral blood leukocytes, but the influence of regular exercise on the frequency of T-cells with a senescent phenotype in young and older adults is not known. PURPOSE: To examine the impact of estimated VO2max on the frequency of senescent blood T-cells in young and middle-aged men. METHODS: Twenty young (Y; age: 23.4 ± 3; BMI: 24.6 ± 3) and 20 middle-aged (O; age: 54 ± 3.6; BMI: 26.4 ± 3.4) healthy males provided a fasted resting blood sample, completed an assessment of percentage body fat and a physical activity status questionnaire designed to estimate VO2max. Y and O subjects were then divided into Hi and Lo VO2max groups (VO2max; Y: 51.2 ± 4.4 vs 42.6 ± 2.2 ml·kg-1·min-1; O: 38.7 ± 3.3 vs 29.5 ± 1.3 ml·kg-1·min-1) with n=10 in each group. Isolated lymphocytes were assessed for cell surface expression of senescence (KLRG1+, CD28-, CD57+), naïve (CD45RA+) and memory (CD45RO+) T-cell markers on CD3+ T-cells, CD4+ T-cells and CD8+ T-cells using four-colour flow cytometry. Differences in T-cell phenotype among the 4-groups was analysed by one-way ANOVA. RESULTS: O had a greater proportion of KLRG1+, CD57+, CD28, KLRG1+/CD57+ and CD45RA-/CD45RO+ CD8+ T-cells than Y, regardless of estimated VO2max. No differences in senescent phenotypes were found between the Hi and Lo VO2max groups in Y. In contrast, the Hi VO2max group in O had a significantly lower frequency of CD4+ and CD8+ T-cells expressing KLRG1+ (CD4: 58%; CD8: 23% less), CD57+ (CD4: 71%; CD8: 20% less), CD28- (CD4: 91%; CD8: 24% less), KLRG1+/CD57+ (CD4: 89%; CD8: 26% less) and CD45RA-/CD45RO+ (CD4: 20% less), in comparison to the Lo VO2max group in O. CONCLUSION: A higher estimated VO2max is associated with a lowered frequency of senescent and memory CD4+ and CD8+ T-cells in middle-aged but not younger men. These findings highlight the beneficial effects of regular physical activity on cellular immunity during ageing.

Optimal window of caloric restriction onset limits its beneficial impact on T‐cell senescence in primates

We have recently shown in non-human primates that caloric restriction (CR) initiated during adulthood can delay T-cell aging and preserve naïve CD8 and CD4 T cells into advanced age. An important question is whether CR can be initiated at any time in life, and whether age at the time of onset would modulate the beneficial effects of CR. In the current study, we evaluated the impact of CR started before puberty or during advanced age on T-cell senescence and compared it to the effects of CR started in early adulthood. Our data demonstrate that the beneficial effects of adult-onset CR on T-cell aging were lost by both early and late CR onset. In fact, some of our results suggest that inappropriate initiation of CR may be harmful to the maintenance of T-cell function. This suggests that there may be an optimal window during adulthood where CR can delay immune senescence and improve correlates of immunity in primates.

Telomerase activity of HIV-1–specific CD8+ T cells: constitutive up-regulation in controllers and selective increase by blockade of PD ligand 1 in progressors

AbstractExhaustion of virus-specific T cells may play an important role in the pathophysiology of chronic viral infections. Here, we analyzed telomere length and telomerase activity in HIV-1–specific CD8+ T cells from progressors or controllers to determine underlying molecular pathways of T-cell exhaustion and senescence. Telomere lengths of HIV-1–specific CD8+ T cells from progressors were significantly shorter compared with autologous cytomegalovirus (CMV)/Epstein-Barr virus (EBV)–specific CD8+ T cells or bulk CD8+ T cells, while telomere lengths from controllers significantly exceeded those of autologous bulk CD8+ T cells and reached a similar level as HIV-1–specific CD8+ T cells collected during primary HIV-1 infection. Telomere length stabilization in controllers corresponded to high levels of constitutive telomerase activity, which was associated with preservation of cytotoxic and proliferative properties. Conversely, limited constitutive telomerase activity was observed in HIV-1–specific CD8+ T cells from progressors, although an increase in both telomere length and telomerase activity was achieved in antigenic-peptide–stimulated cells from progressors after blocking the PD-1/PD ligand 1 (PD-L1) pathway. Collectively, these data suggest a causal role of telomere shortening for the functional deficiencies of HIV-1–specific CD8+ T cells in chronic progressive infection, while high constitutive telomerase activities appears to contribute to maintenance of polyfunctional HIV-1–specific CD8+ T cells from HIV-1 controllers.

Clinical and functional characterisation of a novel TNFRSF1A c.605T>A/V173D cleavage site mutation associated with tumour necrosis factor receptor-associated periodic fever syndrome (TRAPS), cardiovascular complications and excellent response to etanercept treatment

Objectives:To study the clinical outcome, treatment response, T-cell subsets and functional consequences of a novel tumour necrosis factor (TNF) receptor type 1 (TNFRSF1A) mutation affecting the receptor cleavage site.Methods:Patients with...

SELDI-TOF-MS ProteinChip array profiling of T-cell clones propagated in long-term culture identifies human profilin-1 as a potential bio-marker of immunosenescence

BackgroundThe adaptive immune response requires waves of T-cell clonal expansion on contact with pathogen and elimination after clearance of the source of antigen. However, lifelong persistent infections with common viruses cause chronic antigenic stimulation which takes its toll on adaptive immunity in late life. Chronic antigenic stress results in deregulation of the T-cell response and accumulation of anergic cells. Longitudinal studies of the elderly show that this impacts on survival. Identifying the nature of the defects in chronically-stimulated T-cells and protein bio-markers of these dysfunctional cells would help to understand age-associated compromised T-cell function (immunosenescence) and facilitate the development of targeted intervention strategies.The purpose of this work was to use surface-enhanced laser desorption/ionization time-of-flight mass spectrometry (SELDI-TOF-MS) to analyse proteins associated with T-cell senescence in order to identify potential bio-markers. Clonal populations of T-cells isolated from elderly octogenarian and centenarian donors were grown in vitro until senescence, and early passage and late passage (pre-senescent) cells were analysed using SELDI-TOF-MS ProteinChip arrays.ResultsDiscriminant analysis identified several protein or peptide peaks in the region of 14.5–16.5 kDa that were associated with T-cell clone senescence. Human profilin-1, a ubiquitous protein associated with actin remodelling and cellular motility was unambiguously identified. Altered expression of profilin-1 in senescent T-cell clones was confirmed by Western blot analysis.ConclusionDue to the proposed roles of profilin-1 in cellular survival, cytoskeleton remodelling, motility, and proliferation, it is hypothesised that differential expression of profilin-1 in ageing may contribute directly to immunosenescence.

Low CD4+ T-cell counts in HIV patients receiving effective antiretroviral therapy are associated with CD4+ T-cell activation and senescence but not with lower effector memory T-cell function

The adverse effects of immune activation on CD4+ T-cell recovery and the relationship between CD4+ T-cell counts and effector T-cell function were examined in HIV-1 patients receiving long-term effective ART. Patients with nadir CD4+ T-cell counts <100/μl, > 12 months on ART and >6 months with <50 HIV RNA copies/ml were stratified by current CD4+ T-cell counts and patients from the lowest (n = 15) and highest (n = 12) tertiles were studied. We assessed proliferation (Ki67), activation (HLA-DR, CD38) and replicative senescence (CD57) by flow cytometry and CD4+ T-cell responses to CMV by IFN-γ ELISpot. Proportions of CD4+ T-cells expressing HLA-DR or CD57 were strong univariate predictors of total (P = 0.0002 and P = 0.002) and naive (P < 0.0001 and P < 0.0001, respectively) CD4+ T-cell counts, suggesting that CD4+ T-cell activation drives the depletion of naive CD4+ T-cells. This was clearest in patients with a small/undetectable thymus. IFN-γ responses to CMV were similar in patients with low or high CD4+ T-cell counts.

Costimulatory Pathways in Rheumatoid Synovitis and T‐Cell Senescence

The pathogenesis of rheumatoid arthritis (RA) is determined by a complex interaction of genetic and environmental factors. Of all risk factors, age has the largest impact. RA occurs most often during the postmenopausal period of life, with incidence rates peaking in the eighth decade. While age is generally accepted as an etiologic factor for failure of immunocompetence, much less is understood about the role of T-cell senescence in autoimmunity. We have hypothesized that senescent T cells are particularly prone to be activated in specialized microenvironments, such as the synovial membrane. CD4 T cells in the senescence program were identified by the loss of CD28. Gene expression profiling documented that CD28- T cells have acquired a spectrum of regulatory receptors that are usually seen only on NK cells. Such regulatory receptors include stimulatory and inhibitory members of the killer immunoglobulin-like receptor (KIR) family, the stimulatory c-type lectin receptor NKG2D, and CX3CR1, the receptor for the chemokine fractalkine. Synovial fibroblasts express the relevant ligands, thus providing stimulatory signals to tissue-infiltrating T cells. The signaling pathways of these regulatory receptors are complex and dependent on the individual T cells, some of which express important adapter molecules such as DAP10 and DAP12. Inhibitory KIRs on T cells are often only partially functional. Our data suggest that, by virtue of altered receptor profiles, conventional tolerance mechanisms can be evaded in the aging host. By acquiring a new set of regulatory receptors, senescent CD4 T cells become responsive to novel environmental cues and find ideal stimulatory conditions in the synovial microenvironment.

CD8 T-cell immune phenotype of successful aging

The nonagenarian population by definition represents individuals who have demonstrated success in aging. We determined the status of CD8 + T-cell senescence in nonagenarians by analyzing the expression of CD28 and Fas (CD95), and analyzing activation and activation-induced cell death (AICD). Peripheral blood mononuclear cells (PBMCs) were isolated from three groups of subjects: adults (20–64-year-old), older adults (65–89-year-old), and nonagenarians (≥90-year-old). PBMCs were stimulated with phytohemagglutinin (PHA) (10 μg/ml). The cells were labeled with conjugated antibodies specific for CD4, CD8, CD28, CD45RO, and Fas, and were analyzed by FACS ®. There was a strong negative correlation of the percentage of CD28 +Fas − CD8 + T-cells with the age of each individual prior to stimulation in vitro ( R 2 = 0.76, p < 0.0001). Compared to other biomarkers (CD28 −, CD28 −CD45RO +, and Fas +) that have been associated with CD8 + T-cell aging, the loss of the CD28 +Fas − CD8 + T-cell population exhibited the strongest correlation with the individual's chronologic age. After stimulation with PHA, there was a decrease in the percentage of CD8 + T-cells from individual ≥65-year-old that expresses both CD28 + and Fas + at day 3. Surprisingly, the AICD response of CD8 + T-cells at day 7 in the nonagenarians was higher than that in the other two groups. These results suggest that successful aging does not prevent development of the senescent phenotype of unstimulated CD8 + T cells, but is associated with preservation of CD8 T cell functions including activation and AICD. Increased AICD may result in enhanced rejuvenation capacity of T cells and limit the impact of aging on T cell function in nonagenarians.

Human aging alters the first phase of the molecular response to stress in T-cells

This study examines how age affects the first phase of the heat shock response in human T-cells. To understand how age alters transcriptional regulation of the heat shock genes, a cross-sectional study was conducted utilizing human T-cells enriched from peripheral blood lymphocytes of healthy young (20–40 years old) and old (>70 years old) donors. Nuclear run-on analysis revealed a 66% reduction in hsp70 transcription rates in old compared to young nuclei harvested from T-cells exposed to a brief 42 °C heat shock. To determine if one or more protein transactivators of the proximal and distal promoter regions of the hsp70 gene were affected by age, gel shift analysis was performed. Both HSF1 and SP1 DNA-binding were reduced with age but no reduction was noted in CCAAT–DNA binding. Western blot analysis indicated that HSF1 but not HSF2 protein levels were reduced in aged donor samples. These data suggest that human T-cell senescence involves a multi-factorial mechanism that diminishes an important transcriptional response to thermal stress. The results are discussed relative to recent studies that support a multi-factorial mechanism for age-dependent attenuation of the heat shock transcription factor.

Off balance: T-cells in antineutrophil cytoplasmic antibody (ANCA)-associated vasculitides.

There is substantial evidence that T-cells are off balance in antineutrophil cytoplasmic antibody (ANCA)-associated vasculitides. Genetic risk factors may influence shaping of the TCR repertoire and regulatory control of T-cells in predisposed individuals. T-cells are found in inflammatory lesions. Vigorous Th1-type responses are seen in Wegener's granulomatosis and microscopic angiitis, whereas a Th2-type response predominates in Churg-Strauss syndrome. Oligoclonality and shortened telomers indicate antigen-driven clonal expansion and replicative senescence of T-cells in ANCA-associated vasculitides. Potent CD28(-) Th1-type cells displaying an effector-memory/late differentiated, senescent phenotype are expanded in peripheral blood and are found in granulomatous lesions in Wegener's granulomatosis. Differences in proliferative peripheral blood T-cell responses to the autoantigens proteinase 3 (PR3)- and myeloperoxidase (MPO) have not consistently been detected between patients with ANCA-associated vasculitides and healthy controls in vitro. To recognize an autoantigen, break tolerance, and maintain autoimmune disease T- and B-cells require particular triggers and lymphoid structures. There is preliminary evidence of lymphoid-like structures and possible maturation of autoreactive PR3-ANCA-specific B-cells in granulomatous lesions in Wegener's granulomatosis. Alteration of the T-cell response and anomalous autoantigen-presentation in lymphoid-structures could facilitate development of autoimmune disease in ANCA-associated vasculitides.

T-cell senescence: a culprit of immune abnormalities in chronic inflammation and persistent infection

Long-lived clonal T cells deficient in CD28 expression are commonly found in patients with inflammatory syndromes and persistent infections. Considering that CD28 loss is the most consistent immunological marker of aging, we propose that, in pathological states, CD28 null T cells represent prematurely senescent cells resulting from persistent immune activation. These unusual lymphocytes have aberrant functions that contribute to disease-related immune abnormalities, and the degree of accumulation of CD28 null T cells predicts the severity of clinical manifestations. We suggest that understanding of the biological properties of T cells that have reached replicative senescence will influence the future management of certain diseases. Indeed, studies on the molecular basis for the loss of CD28 are already providing information on methods to functionally rescue senescent T cells.

Aging, autoimmunity and arthritis: T-cell senescence and contraction of T-cell repertoire diversity - catalysts of autoimmunity and chronic inflammation.

Rheumatoid arthritis (RA), like many other autoimmune syndromes, is a disease of adults, with the highest incidence rates reported in the elderly. The immune system undergoes profound changes with advancing age that are beginning to be understood and that need to be incorporated into the pathogenetic models of RA. The age-related decline in thymic function causes extensive remodeling of the T-cell system. Age-dependent changes in T-cell homeostasis are accelerated in patients with RA. The repertoire of naive and memory T cells is less diverse, possibly as a result of thymic insufficiency, and it is biased towards autoreactive cells. Presenescent T cells emerge that are resistant to apoptosis and that often expand to large clonal populations. These cells are under the regulatory control of nonconventional costimulatory molecules, display potent effector functions, and appear to be critical in the synovial and extra-articular manifestations of RA.

Cell death and longevity: implications of Fas-mediated apoptosis in T-cell senescence.

Two prominent features of immune senescence are altered T-cell phenotype and reduced T-cell response. We have previously shown that T-cell senescence is greatly reduced in CD2-fas transgenic mice, in which the Fas apoptosis molecule is constantly expressed on T cells. Using a different experimental approach, the relationship between T-cell senescence and apoptosis was analyzed on human peripheral blood mononuclear cells. The results indicate that there was increased apoptosis of CD45RO- (CD45RA+) T cells upon activation. We propose that this could account for the increase in CD45RO+ "memory" T cells with aging in humans. T-cell responsiveness remained high in CD2-fas transgenic aged mice, but there was no increase in overall life span of these mice. Increased T-cell responsiveness was associated with an increased acute-phase response and serum amyloid A deposition in the glomerulus of aged CD2-fas transgenic mice. Therefore, restoration of the T-cell immune function using a CD2-fas transgene produced undesirable side-effects to aged transgenic mice. In addition to its role in activation-induced cell death, Fas-mediated apoptosis may be important in deleting T cells in response to DNA damage. It may also inhibit cell-cycle progression by cleaving various kinases and DNA repair enzymes. We observed that cell lines derived from human premature aging diseases have a higher sensitivity to Fas-mediated apoptosis. The implications of these observations are discussed.

Clinical features associated with correction of T-cell senescence: Increased acute-phase response, amyloidosis and arthritis

Two prominent features associated with immunosenescence are thymic involution and altered T-cell phenotype and responsiveness. We have shown previously that in CD2- fas transgenic mice, in which the Fas apoptosis molecule is constituatively expressed on T cells, T-cell senescence is greatly reduced. Using a different experimental approach, the relationship between T-cell senescence and apoptosis was analyzed on human PBMCs. The results indicate that there was increased apoptosis of CD45RO − (CD45RA +) T cells upon activation. We propose that this could account for the increase in CD45RO + ‘memory’ T cells with aging in humans. Together these results are consistent with the notion that T-cell senescence is associated with altered apoptosis and decreased T-cell responsiveness. T-cell responsiveness remained high in CD2- fas transgenic aged mice, but there was no increase in overall life span of the mice. Increased T-cell responsiveness was associated with an increased acute-phase response and amyloid A deposition in the glomerulus of these mice. These data suggest that restoration of the T-cell immune function in aged individuals must be carried out in concert with correction of other immune factors that down modulate the acute-phase response to prevent undesirable side-effects.