Decline in CD28+ T cells in centenarians and in long-term T cell cultures: A possible cause for both in vivo and in vitro immunosenescence

Effros, Rita B.; Boucher, Nathalie; Porter, Verna; Zhu, Xiaoming; Spaulding, Carolyn; Walford, Roy L.; Kronenberg, Mitchell; Cohen, Daniel; Schächter, François

doi:10.1016/0531-5565(94)90073-6

Cited by 341 publications

(193 citation statements)

References 19 publications

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“…Even at the age of 65, decades after the involution of the thymus, both naïve and memory CD4 T cells are highly diverse and show no contraction in T-cell receptor diversity compared to young adults [10]. Also, the classical phenotypic change of CD28 loss, frequently encountered in CD8 T cells with age [17], is only inconsistently seen for CD4 T cells [11]. However, the molecular mechanisms regulating CD28 expression and loss appear to be identical in both T-cell subsets [29;30], suggesting a fundamental difference in CD4 and CD8 T cells in response to aging, possibly in addition to distinct cell-specific transcriptional regulation.…”

Section: Introductionmentioning

confidence: 99%

T cell subset-specific susceptibility to aging

Cześnikiewicz-Guzik

Lee

Cui

et al. 2008

Clinical Immunology

379

327

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With increasing age, the competence of the immune system to fight infections and tumors declines. Age-dependent changes have been mostly described for human CD8 T cells, raising the question of whether the response patterns for CD4 T cells are different. Gene expression arrays of memory CD4 T cells yielded a similar age-induced fingerprint as has been described for CD8 T cells. In crosssectional studies, the phenotypic changes were not qualitatively different for CD4 and CD8 T cells, but occurred much more frequently in CD8 T cells. Homeostatic stability partially explained this lesser age sensitivity of CD4 T cells. With aging, naïve and central memory CD8 T cells were lost at the expense of phenotypically distinct CD8 effector T cells, while effector CD4 T cells did not accumulate. However, phenotypic shifts on central memory T cells were also more pronounced in CD8 T cells. This distinct stability in cell surface marker expression can be reproduced in vitro. The data show that CD8 T cells are age sensitive by at least two partially independent mechanisms: fragile homeostatic control and gene expression instability in a large set of regulatory cell surface molecules.

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Section: Introductionmentioning

confidence: 99%

T cell subset-specific susceptibility to aging

Cześnikiewicz-Guzik

Lee

Cui

et al. 2008

Clinical Immunology

379

327

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“…Both aging and HIV are associated with immune senescence and loss of responsiveness (Effros et al, 1994;Effros & Pawelec, 1997), and both are also associated with disruption of neuroendocrine inputs to the immune system (Kumar et al, 2002;Madden, Thyagarajan, & Felten, 1998). The loss of self-regulation in disease and aging likely makes affected people more susceptible to negative immunological effects of stress.…”

Section: Individual Differences and Immune Change Under Stressmentioning

confidence: 99%

Psychological Stress and the Human Immune System: A Meta-Analytic Study of 30 Years of Inquiry.

Segerstrom

Miller

2004

Psychological Bulletin

2,512

1,824

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The present report meta-analyzes more than 300 empirical articles describing a relationship between psychological stress and parameters of the immune system in human participants. Acute stressors (lasting minutes) were associated with potentially adaptive upregulation of some parameters of natural immunity and downregulation of some functions of specific immunity. Brief naturalistic stressors (such as exams) tended to suppress cellular immunity while preserving humoral immunity. Chronic stressors were associated with suppression of both cellular and humoral measures. Effects of event sequences varied according to the kind of event (trauma vs. loss). Subjective reports of stress generally did not associate with immune change. In some cases, physical vulnerability as a function of age or disease also increased vulnerability to immune change during stressors.Since the dawn of time, organisms have been subject to evolutionary pressure from the environment. The ability to respond to environmental threats or stressors such as predation or natural disaster enhanced survival and therefore reproductive capacity, and physiological responses that supported such responses could be selected for. In mammals, these responses include changes that increase the delivery of oxygen and glucose to the heart and the large skeletal muscles. The result is physiological support for adaptive behaviors such as "fight or flight." Immune responses to stressful situations may be part of these adaptive responses because, in addition to the risk inherent in the situation (e.g., a predator), fighting and fleeing carries the risk of injury and subsequent entry of infectious agents into the bloodstream or skin. Any wound in the skin is likely to contain pathogens that could multiply and cause infection (Williams & Leaper, 1998). Stress-induced changes in the immune system that could accelerate wound repair and help prevent infections from taking hold would therefore be adaptive and selected along with other physiological changes that increased evolutionary fitness.Modern humans rarely encounter many of the stimuli that commonly evoked fight-or-flight responses for their ancestors, such as predation or inclement weather without protection. However, human physiological response continues to reflect the demands of earlier environments. Threats that do not require a physical response (e.g., academic exams) may therefore have physical consequences, including changes in the immune system. Indeed, over the past 30 years, more than 300 studies have been done on stress and immunity in humans, and together they have shown that psychological challenges are capable of modifying various features of the immune response. In this article we attempt to consolidate empirical knowledge about psychological stress and the human immune system through meta-analysis. Both the construct of stress and the human immune system are complex, and both could consume bookCorrespondence concerning this article should be addressed to Suzanne C. Segerstrom, Department of Ps...

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“…Senescent fibroblasts, for example, enhance the growth of tumor cells both in vitro and in vivo [7]. In the case of CD8 T cell cultures, senescence is associated with enhanced production of two pro-inflammatory cytokines, IL-6 and TNFα, and reduced secretion of the anti-viral cytokine, interferon γ [8] Arguably, the most significant genetic and phenotypic alteration associated with T cell replicative senescence in cell culture is the complete and irreversible loss of expression of the CD28 costimulatory molecule [9]. This permanent loss of any detectible CD28 surface and message expression is in contrast to the well-documented up-and down-regulation of the quantity of CD28 surface expression associated with physiological activation [10][11][12][13][14].…”

Section: Replicative Senescence: the In Vitro Modelmentioning

confidence: 99%

Telomerase induction in T cells: A cure for aging and disease?

Effros

2007

Experimental Gerontology

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Cells of the immune system are unique among normal somatic cells in that they have the capacity to upregulate the telomere-extending enzyme, telomerase, albeit in a precisely controlled fashion. Kinetic analysis of telomerase activity in long-term T cell cultures has documented that the high level of telomerase induced in concert with activation reaches a peak at 3-5 days, then declines by 3 weeks. The process is recapitulated during secondary antigenic stimulation, but by the third, and all subsequent stimulations in vitro, CD8 T cells are unable to upregulate telomerase. Cell division in the absence of telomerase activity results in progressive telomere shortening, and ultimately, the DNA damage/cell cycle arrest that is signaled by critically short telomeres. Cultures of senescent CD8 T cells show altered cytokine patterns, resistance to apoptosis, and absence of expression of the CD28 co-stimulatory receptor. CD8 T cells with these and other features of replicative senescence accumulate progressively with age, and at an accelerated rate, during chronic infection with HIV-1. Clinical studies have shown that high proportions of CD8 T cells with the senescent phenotype correlate with several deleterious physiologic outcomes, including poor vaccine responses, bone loss, and increased proinflammatory cytokines. CD8 + CD28 − T cells have also been shown to exert suppressive activity on other immune cells. Based on the central role of telomere shortening in the replicative senescence program, we are developing several telomerase-based approaches as potential immunoenhancing treatments for aging and HIV disease. Gene therapy of HIV-specific CD8 T cells with the telomerase catalytic component (hTERT) results in enhanced proliferative capacity, increased anti-viral functions, and a delay in the loss of CD28 expression, with no changes in karyotype or growth kinetics. These proof-of-principle studies have led to screening for pharmacological approaches that might mimic the gene therapy effects, in a more clinically-suitable formulation.

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Decline in CD28+ T cells in centenarians and in long-term T cell cultures: A possible cause for both in vivo and in vitro immunosenescence

Cited by 341 publications

References 19 publications

T cell subset-specific susceptibility to aging

T cell subset-specific susceptibility to aging

Psychological Stress and the Human Immune System: A Meta-Analytic Study of 30 Years of Inquiry.

Telomerase induction in T cells: A cure for aging and disease?

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