1056 T CELLS and AGING, JANUARY 2002 UPDATE Graham
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[Frontiers in Bioscience 7, d1056-1183, May 1, 2002] T CELLS AND AGING, JANUARY 2002 UPDATE Graham Pawelec1, Yvonne Barnett2, Ros Forsey3, Daniela Frasca4, Amiela Globerson5, Julie McLeod6, Calogero Caruso7, Claudio Franceschi8, Támás Fülöp9, Sudhir Gupta10, Erminia Mariani8, Eugenio Mocchegiani11, Rafael Solana12 1University of Tübingen, Center for Medical Research, ZMF, Waldhörnlestr. 22, D-72072 Tübingen, Germany, 2 University of Ulster, Coleraine, UK, 3 Unilever Research, Bedford, UK, 4 University of Miami, FL, 5 University of the Negev, Israel, 6 University of the West of England, Bristol, UK, 7 University of Palermo, Italy, 8 University of Bologna, Italy, 9 University of Sherbrooke, Quebec, Canada, 10 University of California, Irvine, CA, 11 INRCA, Ancona, Italy, 12 University of Córdoba, Spain TABLE OF CONTENTS 1. Abstract 2. Introduction: How do we establish whether immunosenescence exists and if so whether it means anything to immunological defence mechanisms in aging? 3. Factors contributing to immunosenescence 3.1. Hematopoiesis 3.2. Thymus 4. Post-thymic aging 4.1. T cell subsets 4.2. T cell repertoire 4.3. T cell function 4.3.1. Accessory cells 4.3.2. T cell receptor signal transduction 4.3.3. Costimulatory pathways 4.3.3.1. CD28 family coreceptors and CD80 family ligands 4.3.3.2. Other costimulators 4.4. Cytokine production and response 4.4.1. Regulation of gene transcription 4.4.2. Cytokine secretion 4.4.3. Confounding factors affecting cytokine secretion results 4.4.4. Levels of cytokines in plasma 4.4.5. Cytokine antagonists 4.4.6. Cytokine receptor expression 5. Clonal expansion after T cell activation 5.1. Culture models for immunosenescence: does the Hayflick Limit apply to normal T cells and if not, why not? 5.2. Does telomere attrition contribute to the replicative senescence of normal T cells? 5.3. Longevity of naive and memory cells 5.4 . Activation-induced cell death and aging 6. Clinical relevance of immunosenescence 6.1. Infectious disease and cancer 6.2.. Vaccination 6.3. Benefits of immunosenescence? 6.4 . Autoimmunity 6.5. Predictors of mortality and longevity 7. Possible approaches to remediation 7.1. Vitamins and minerals; antioxidants; "nutriceuticals" 7.2. Hormones 7.3. Caloric restriction without malnutrition 7.4. Mutations and DNA repair; cell cycle control 7.5. Recombinant cytokines 7.6 . Stress 7.7 .Other approaches – gene therapy 8. Conclusions 9. Acknowledgements 10. References 1. ABSTRACT Age-related changes in the immune system may aged. Many studies mostly performed in mice, rats and man contribute to morbidity and mortality due to decreased but also including monkeys and dogs have established that resistance to infection and, possibly, certain cancers in the age-associated immune decline is characterized 1056 T cell immunosenescence bydecreases in both humoral and cellular responses. The critically-short telomeres. However, mouse cells either stop former may be largely a result of the latter, because growing for other reasons or undergo transformation observed changes both in the B cell germline-encoded (“immortalisation”) in culture. In humans, loss of telomeric repertoire and the age-associated decrease in somatic repeats triggers a completely different set of growth hypermutation of the B cell antigen receptors are now arrest/apoptosis processes. These considerations alone known to be critically affected by helper T cell aging. As make comparisons between humans and mice difficult; antigen presenting cell (APC) function appears to be well- certainly there are species-related differences which have maintained in the elderly, this review will focus on the T not yet been elucidated. The current update of this review cell. Factors contributing to T cell immunosenescence may will build on the previous version (February 1999) to cover include a) altered production of T cell progenitors (stem the most recent work on immunosenescence in man, but cell defects, stromal cell defects), b) decreased levels of reference to studies in mice and other species are newly-generated mature T cells (thymic involution), c) inevitable; the latter must be viewed in the light of the aging of resting immune cells, d) disrupted activation above considerations. pathways in immune cells (stimulation via the T cell receptor for antigen, costimulation, apoptosis control), e) The changes of immune status in the elderly are replicative senescence of clonally expanding cells. This generally perceived as reflecting a deterioration of immune review aims to consider the current state of knowledge on function (hence the common term “immunosenescence”), the scientific basis for and potential clinical relevance of but it remains controversial whether they themselves cause those factors in immunosenescence in humans. or are caused by underlying disease in humans. Despite Experiments in other species will be touched upon with the strenuous efforts to circumvent this problem by separating proviso that there are clearly differences between them, “disease” from “aging”, as exemplified by the application especially between humans and rodents, but exactly what of the “SENIEUR” protocol and its modifications (3,4), this those differences are is not completely clear. Given its problem is not solved. Although extremely healthy potential importance and the increasing proportion of “successfully” aged people may still behave elderly people the world over, coupled with the realisation immunologically differently from the young, this may not that whereas mortality is decreasing, morbidity may not be necessarily impact on clinically important health decreasing in parallel (1), a better understanding of the parameters (5,6). The whole question of proband selection causes and impact of immunosenescence may offer the for immunogerontological studies is the subject of much possibility of identifying where prevention or delay of discussion, for example, see the recent series of onset, as well as therapeutic intervention, might be commentary articles in Mech Aging Dev (7-10). beneficial. Amelioration of the effects of dysregulated immune responses in the elderly by replacement therapy, Many years ago, it was established that several supplementation therapy or other approaches may result in tests of T cell function give different results in the elderly an enhancement of their quality of life, and significant than in the young, and this was interpreted as indicating reductions in the cost of medical care in old age. depressed responses in elderly individuals (11). Even such very strong reactions as the rejection of allogeneic skin 2. INTRODUCTION: HOW DO WE ESTABLISH transplants in mice (12) and rats (13) and alloantigen WHETHER IMMUNOSENESCENCE EXISTS AND recognition In vitro (14) may be depressed. Particularly the IF SO WHETHER IT IS RELEVANT TO ability of T cells to undergo clonal expansion when IMMUNOLOGICAL DEFENCE MECHANISMS IN stimulated In vitro is repeatedly identified as an age- AGING? associated decrease in immune function. Various mechanisms have been proposed to account for such T cell function is altered In vivo and In vitro in suboptimal proliferation but they probably still offer only elderly compared to young individuals. This is found in an incomplete explanation of this phenomenon. both long and short-lived species as a function of their age Nonetheless, several early studies already suggested a relative to life-expectancy rather than chronological time positive association between T cell function as it could be (2). Why should similar changes which occur over 100 measured In vitro, and individual longevity (15-17), and years in humans take place more rapidly during 3 years in between absolute lymphocyte counts and longevity (18). In mice, were these changes not in some way pre- these and very many other studies, the “chicken and egg” programmed? On the other hand, the relative lack of question has to be asked: ie. do people live longer because antioxidant defences in short-lived mice compared to long- of “good” T cell function, or do they possess good T cell lived humans, whereby mouse cells are much more function because other factors have enabled them to survive susceptible to oxidative damage and malignant longer? This question remains difficult to answer even transformation, might suggest that deleterious changes are today, and even in mice, which are of course easier to study simply occurring faster in the former. Another difference than humans. One problem is that immunogerontology between these species is that mouse cells (at least those relies on two main types of study design, cross-sectional from commonly-used laboratory strains) possess and longitudinal. The former is easier and faster to perform exceptionally long stretches of telomeric repeats at the end but may result in comparing heterogeneous populations of their chromosomes, whereas those of humans are much (genetically and environmentally). For this reason, most shorter. This should give mouse cells the advantage in information that we have on human immunosenescence is terms of number of cell divisions that telomerase-negative derived from cross-sectional studies. Thus, one cannot be cells can undergo prior to growth arrest caused by sure that any age-associated alterations identified are not in 1057 T cell immunosenescence fact due to selection for other traits in the population. the health status of the subjects. For this purpose, the Centenarians as a model of successful aging are an extreme SENIEUR protocol, as mentioned above, is a strict donor