Immunity and age: living in the past?
Authors: David L. Woodland, Marcia A. Blackman
Journal: Trends in Immunology (2006)

Increasing age is associated with a decreasing ability to mediate effective immune responses to newly encountered antigens. It is generally believed that this reflects the age-associated decline in the number, repertoire and function of available naive T cells. Here, we propose that naive T cells become increasingly irrelevant to the immune system, and that responses to newly encountered antigens are progressively dominated by cross-reactive memory T cells as the individual ages. In addition, we propose that the majority, if not all, of the response to newly encountered antigens in the elderly is mediated by cross-reactive memory T cells. This predicts highly stochastic responses to new infections that should vary between individuals, and has important implications for vaccination strategies in the elderly. Increasing age is associated with a decreasing ability to mediate effective immune responses to newly encountered antigens. It is generally believed that this reflects the age-associated decline in the number, repertoire and function of available naive T cells. Here, we propose that naive T cells become increasingly irrelevant to the immune system, and that responses to newly encountered antigens are progressively dominated by cross-reactive memory T cells as the individual ages. In addition, we propose that the majority, if not all, of the response to newly encountered antigens in the elderly is mediated by cross-reactive memory T cells. This predicts highly stochastic responses to new infections that should vary between individuals, and has important implications for vaccination strategies in the elderly. It has been well documented that increasing age is associated with a decline in humoral and cell-mediated immunity to newly encountered pathogens or vaccines [1Linton P.J. Dorshkind K. Age-related changes in lymphocyte development and function.Nat. 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Problems and solutions to the development of vaccines in the elderly.Immunol. Allergy Clin. North Am. 2003; 23: 41-55Abstract Full Text Full Text PDF PubMed Scopus (19) Google Scholar, 14Murasko D.M. Jiang J. Response of aged mice to primary virus infections.Immunol. Rev. 2005; 205: 285-296Crossref PubMed Scopus (76) Google Scholar]. This decline in immune responsiveness is a significant clinical problem because the elderly become highly susceptible to infection and, simultaneously, tend to be less responsive to vaccines. For example, the elderly are particularly susceptible to the secondary effects of influenza infection, and influenza vaccines are documented to be comparatively ineffective in the elderly [8Phair J. et al.Failure to respond to influenza vaccine in the aged: correlation with B-cell number and function.J. Lab. Clin. Med. 1978; 92: 822-828PubMed Google Scholar, 10Murasko D.M. et al.Role of humoral and cell-mediated immunity in protection from influenza disease after immunization of healthy elderly.Exp. Gerontol. 2002; 37: 427-439Crossref PubMed Scopus (211) Google Scholar, 15McElhaney J.E. The unmet need in the elderly: designing new influenza vaccines for older adults.Vaccine. 2005; 23: S10-S25Crossref PubMed Scopus (153) Google Scholar, 16McElhaney J.E. Overcoming the challenges of immunosenescence in the prevention of acute respiratory illness in older people.Conn. Med. 2003; 67: 469-474PubMed Google Scholar]. Clearly, a thorough understanding of the factors that affect immune responsiveness in the elderly is important for developing vaccines that target this population. The generation of a vigorous immune response to newly encountered pathogens depends on both the function and repertoire diversity of naive T cells. T cells must be able to proliferate in response to antigen, acquire appropriate effector responses (such as the production of cytokines and the delivery of T-cell help) and be able to migrate to the appropriate effector site. In addition, at the population level, naive T cells need to express a diverse array of T-cell receptors to ensure the recognition of appropriate antigenic determinants in the pathogen. Whereas the pool of naive T cells in young individuals generally fulfills these criteria, there is accumulating evidence that naive CD4+ and CD8+T cells in aged individuals become increasingly compromised in their effector function and repertoire diversity. First, naive T cells in aged individuals exhibit significantly impaired proliferative responses and capacity to mediate pathogen clearance, graft rejection, delayed hypersensitivity and tumor rejection [5Miller R.A. The aging immune system: primer and prospectus.Science. 1996; 273: 70-74Crossref PubMed Scopus (1020) Google Scholar, 17Po J.L. et al.Age-associated decrease in virus-specific CD8+T lymphocytes during primary influenza infection.Mech. Ageing Dev. 2002; 123: 1167-1181Crossref PubMed Scopus (70) Google Scholar, 18Haynes L. Eaton S.M. The effect of age on the cognate function of CD4+T cells.Immunol. Rev. 2005; 205: 220-228Crossref PubMed Scopus (103) Google Scholar]. In addition, studies of the humoral response in experimental animals and humans have shown that aged individuals have a significantly reduced ability to initiate an effective antibody response following infection or vaccination, presumably a consequence of dysfunctional aged CD4+T-cell 'help' [19Johnson S.A. Cambier J.C. Ageing, autoimmunity and arthritis: senescence of the B cell compartment – implications for humoral immunity.Arthritis Res. Ther. 2004; 6: 131-139Crossref PubMed Google Scholar, 20High K.P. Infection as a cause of age-related morbidity and mortality.Ageing Res. Rev. 2004; 3: 1-14Crossref PubMed Scopus (75) Google Scholar]. Second, the numbers of naive T cells are profoundly reduced during aging, resulting in limitations in the breadth of the naive T-cell repertoire. This is believed to be a consequence of thymic involution, which results in the decreasing production of new naive T cells [21Naylor K. et al.The influence of age on T cell generation and TCR diversity.J. Immunol. 2005; 174: 7446-7452PubMed Google Scholar]. Importantly, the decline in naive T-cell numbers could result in a weaker and more-stochastic response, because the numbers of naive T cells capable of responding to a particular antigen could drop below a necessary threshold. Thus, it is apparent that the aging individual not only has fewer naive T cells but that these cells are less functional and show reduced diversity, in terms of antigen-specificity, than the equivalent cells in young individuals. A question raised by the age-related physiological changes in naive T-cell numbers and function is to what extent they alter the T-cell response to newly encountered antigens. One possible factor that is not generally considered when addressing this question is the impact of memory T cells. A major characteristic of the aging immune system is that the ratio of naive to memory T cells becomes dramatically skewed in favor of memory cells [21Naylor K. et al.The influence of age on T cell generation and TCR diversity.J. Immunol. 2005; 174: 7446-7452PubMed Google Scholar, 22Lerner A. et al.Pgp-1hi T lymphocytes accumulate with age in mice and respond poorly to concanavalin A.Eur. J. Immunol. 1989; 19: 977-982Crossref PubMed Scopus (275) Google Scholar, 23Globerson A. Effros R.B. Ageing of lymphocytes and lymphocytes in the aged.Immunol. Today. 2000; 21: 515-521Abstract Full Text Full Text PDF PubMed Scopus (278) Google Scholar]. This is partly caused by the increasing antigen experience of the individual and the associated decline in numbers of naive T cells. We speculate that the increasing dominance of the memory T-cell pool forces competition between naive T cells and fortuitously cross-reactive memory T cells in mediating responses to newly encountered antigens. Whereas this competition strongly favors naive T cells in young mice, which have a limited memory T-cell pool and a robust naive T-cell pool, we propose that this competition progressively favors memory T cells during aging. In addition, we propose that memory T cells comprise the majority, if not all, of the primary T-cell response to newly encountered antigens in aged individuals. Several lines of evidence support this basic idea. (i) The T-cell immune systems of the elderly are comprised predominantly of memory cells. There are three major factors that contribute to the gradual skewing of the repertoire from largely naive in neonates to mainly antigen-experienced and memory in the elderly. First, a hallmark of the aging immune system is the progressive involution of the thymus and the corresponding decline in the production of new thymic emigrants [3Miller R.A. Aging and immune function.Int. Rev. Cytol. 1991; 124: 187-215Crossref PubMed Scopus (281) Google Scholar, 24Haynes B.F. et al.The role of the thymus in immune reconstitution in aging, bone marrow transplantation, and HIV-1 infection.Annu. Rev. Immunol. 2000; 18: 529-560Crossref PubMed Scopus (428) Google Scholar]. By a certain age, thymic output can cease completely, although there could be other sites of naive T-cell development [25Berzins S.P. et al.A central role for thymic emigrants in peripheral T cell homeostasis.Proc. Natl. Acad. Sci. U. S. 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The dramatic decline in naive T-cell numbers after 65 years of age is probably owing to further age-associated changes in the homeostatic proliferation of naive T cells and increased spontaneous T-cell activation [21Naylor K. et al.The influence of age on T cell generation and TCR diversity.J. Immunol. 2005; 174: 7446-7452PubMed Google Scholar, 29Tanchot C. et al.Lymphocyte homeostasis.Semin. Immunol. 1997; 9: 331-337Crossref PubMed Scopus (131) Google Scholar, 30Surh C.D. Sprent J. Regulation of naive and memory T-cell homeostasis.Microbes Infect. 2002; 4: 51-56Crossref PubMed Scopus (67) Google Scholar]. Consequently, the naive T-cell pool represents an increasingly smaller proportion of the total number of available T cells with aging. Indeed, in people older than 100 years of age, naive CD8+T cells are essentially absent [31Fagnoni F.F. et al.Shortage of circulating naive CD8+T cells provides new insights on immunodeficiency in aging.Blood. 2000; 95: 2860-2868Crossref PubMed Google Scholar]. Second, there is an increasing representation of T cells with a memory phenotype, driven largely by the accumulated experience of the individual with pathogenic challenge and by the homeostatic proliferation of the memory T-cell pool [21Naylor K. et al.The influence of age on T cell generation and TCR diversity.J. Immunol. 2005; 174: 7446-7452PubMed Google Scholar]. For example, in the murine system, the ratio of memory to naive CD8+T cells already approaches 90% by 18 months, which is much lower than the upper age limit of laboratory mice (E. Yager, D. Woodland and M. Blackman, unpublished). The age-associated emergence of dominant clones, largely of CD8+T cells, could also have an important role in establishing the dominance of the memory T-cell pool [32Posnett D.N. et al.Clonal populations of T cells in normal elderly humans: the T cell equivalent to 'benign monoclonal gammapathy'.J. Exp. Med. 1994; 179: 609-618Crossref PubMed Scopus (719) Google Scholar, 33Schwab R. et al.Expanded CD4+ and CD8+T cell clones in elderly humans.J. Immunol. 1997; 158: 4493-4499PubMed Google Scholar, 34Callahan J.E. et al.Unexpected expansions of CD8-bearing cells in old mice.J. Immunol. 1993; 151: 6657-6669PubMed Google Scholar, 35Clambey E.T. et al.Non-malignant clonal expansions of CD8+ memory T cells in aged individuals.Immunol. Rev. 2005; 205: 170-189Crossref PubMed Scopus (60) Google Scholar]. These clonal expansions are common in healthy adults and are thought to be driven largely by chronic infections, particularly cytomegalovirus (CMV) [36Khan N. et al.Cytomegalovirus seropositivity drives the CD8 T cell repertoire toward greater clonality in healthy elderly individuals.J. Immunol. 2002; 169: 1984-1992PubMed Google Scholar]. (ii) T-cell responses are known to be highly cross-reactive. Antigen recognition by T cells is extremely degenerate [37Mason D. A very high level of crossreactivity is an essential feature of the T-cell receptor.Immunol. Today. 1998; 19: 395-404Abstract Full Text Full Text PDF PubMed Scopus (782) Google Scholar, 38Nikolich-Zugich J. et al.The many important facets of T-cell repertoire diversity.Nat. Rev. Immunol. 2004; 4: 123-132Crossref PubMed Scopus (491) Google Scholar]. Studies by Selin and co-workers have documented substantial degeneracy in the T-cell responses to viruses, resulting in a large amount of cross-reactivity with apparently unrelated antigens [39Selin L.K. et al.CD8 memory T cells: cross-reactivity and heterologous immunity.Semin. Immunol. 2004; 16: 335-347Crossref PubMed Scopus (98) Google Scholar, 40Selin L.K. Welsh R.M. Plasticity of T cell memory responses to viruses.Immunity. 2004; 20: 5-16Abstract Full Text Full Text PDF PubMed Scopus (90) Google Scholar]. Indeed, cross-reactive memory T-cell responses seem to be the rule instead of the exception for some responses modeled in the mouse, and, in most cases, the cross-reactivity is unpredictable [41Kim S.K. et al.Private specificities of CD8 T cell responses control patterns of heterologous immunity.J. Exp. Med. 2005; 201: 523-533Crossref PubMed Scopus (115) Google Scholar]. Evidence also exists for similar cross-reactive responses to human pathogens, for example, between influenza virus and hepatitis C virus, influenza virus and Epstein–Barr virus (EBV), human papilloma virus and coronavirus, and between different strains of dengue virus [42Wedemeyer H. et al.Cross-reactivity between hepatitis C virus and influenza A virus determinant-specific cytotoxic T cells.J. Virol. 2001; 75: 11392-11400Crossref PubMed Scopus (203) Google Scholar, 43Welsh R.M. et al.Immunological memory to viral infections.Annu. Rev. Immunol. 2004; 22: 711-743Crossref PubMed Scopus (181) Google Scholar, 44Nilges K. et al.Human papillomavirus type 16 E7 peptide-directed CD8+T cells from patients with cervical cancer are cross-reactive with the coronavirus NS2 protein.J. Virol. 2003; 77: 5464-5474Crossref PubMed Scopus (67) Google Scholar, 45Mongkolsapaya J. et al.Original antigenic sin and apoptosis in the pathogenesis of dengue hemorrhagic fever.Nat. 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Invest. 2005; 115: 3602-3612Crossref PubMed Scopus (138) Google Scholar, 48Urbani S. et al.Heterologous T cell immunity in severe hepatitis C virus infection.J. Exp. Med. 2005; 201: 675-680Crossref PubMed Scopus (123) Google Scholar]. For example, cross-reactive responses generally involve a restricted repertoire of T cells, are usually of low avidity (although in rare cases the avidity can actually be increased) and focus on only a few epitopes. They might direct the immune system to focus on subdominant epitopes or result in an excessively immunopathological response to a generally innocuous pathogen. We propose that, with the increasing age-associated constriction of the naive repertoire, the proportion of responses based on cross-reactive memory should increase, and eventually dominate the reactivity pattern of the individual. (iii) Naive T cells but not memory T cells become functionally impaired with age. In addition to progressive changes in the relative numbers of naive and memory T cells, there are also changes in the functional attributes of naive cells [49Hori Y. et al.Decline in phytohemagglutinin responsiveness of spleen cells from aging mice.Proc. Soc. Exp. Biol. Med. 1973; 144: 48-53Crossref PubMed Scopus (107) Google Scholar, 50Murasko D.M. et al.Decline in mitogen induced proliferation of lymphocytes with increasing age.Clin. Exp. Immunol. 1987; 70: 440-448PubMed Google Scholar]. It is well-established that naive CD4+T-cell function declines with age [5Miller R.A. The aging immune system: primer and prospectus.Science. 1996; 273: 70-74Crossref PubMed Scopus (1020) Google Scholar]. Studies by Haynes and colleagues using T-cell receptor transgenic mice indicate that this progressive loss of proliferative activity is caused by a defect in interleukin (IL)-2 production and that proliferative responses can be restored through the addition of exogenous IL-2 [51Haynes L. et al.The defects in effector generation associated with aging can be reversed by addition of IL-2 but not other related γc-receptor binding cytokines.Vaccine. 2000; 18: 1649-1653Crossref PubMed Scopus (50) Google Scholar, 52Haynes L. et al.Interleukin 2, but not other common γ chain-binding cytokines, can reverse the defect in generation of CD4 effector T cells from naive T cells of aged mice.J. Exp. Med. 1999; 190: 1013-1024Crossref PubMed Scopus (207) Google Scholar]. Importantly, this group recently showed that dysfunction in CD4+T cells from aged mice depended on the age of the CD4+T cell and not the age of the mouse, and that newly emerging CD4+T cells in aged mice, induced by CD4 depletion or the construction of bone marrow chimeras, were highly functional [53Haynes L. et al.Newly generated CD4 T cells in aged animals do not exhibit age-related defects in response to antigen.J. Exp. Med. 2005; 201: 845-851Crossref PubMed Scopus (91) Google Scholar]. The impact of age on the function of naive CD8+T cells is less well characterized. Although some reports show an age-associated functional decline [54Effros R.B. Walford R.L. Diminished T-cell response to influenza virus in aged mice.Immunology. 1983; 49: 387-392PubMed Google Scholar, 55Bender B.S. et al.Influenza in senescent mice: impaired cytotoxic T-lymphocyte activity is correlated with prolonged infection.Immunology. 1991; 72: 514-519PubMed Google Scholar], others have found no evidence for dysfunction [56Po J.L.Z. et al.Age-associated decrease in virus-specific CD8+T lymphocytes during primary influenza infection.Mech. Ageing Dev. 2002; 123: 1167-1181Crossref PubMed Scopus (117) Google Scholar, 57Li S.P. et al.Early antigen-specific response by naive CD8 T cells is not altered with aging.J. Immunol. 2002; 168: 6120-6127PubMed Google Scholar]. Also, it is unclear whether reported deficiencies result from reduced numbers of CD8+T cells recruited to the response or functional impairment on a per-cell basis. It is also unknown whether functional defects are inherent to CD8+T cells or are a consequence of functionally defective CD4+T cells. It is currently possible that the failure of the thymus to produce new naive T cells forces the existing pool to continually replicate by homeostatic mechanisms to maintain the naive pool. This could induce the observed impairment and also further limit the available T-cell repertoire. In contrast to naive T cells, memory T cells retain their capacity to mediate effector responses over the long-term, and, in the case of CD8+T cells, actually increase in efficacy over time on a per-cell basis [58Kapasi Z.F. et al.Defective generation but normal maintenance of memory T cells in old mice.Eur. J. Immunol. 2002; 32: 1567-1573Crossref PubMed Scopus (101) Google Scholar, 59Roberts A.D. et al.Differential contributions of central and effector memory T cells to recall responses.J. Exp. Med. 2005; 202: 123-133Crossref PubMed Scopus (225) Google Scholar]. Even though the absolute numbers of memory T cells for a given pathogen can decline over time, the constant exposure of the host to pathogens ensures a robust memory T-cell pool [60Hammarlund E. et al.Duration of antiviral immunity after smallpox vaccination.Nat. Med. 2003; 9: 1131-1137Crossref PubMed Scopus (737) Google Scholar, 61Homann D. et al.Differential regulation of antiviral T-cell immunity results in stable CD8+ but declining CD4+T-cell memory.Nat. Med. 2001; 7: 913-919Crossref PubMed Scopus (500) Google Scholar]. The exception to this rule is that some memory cells in aged individuals undergo dramatic clonal expansions, and some of these cells can exhibit impaired function [62Messaoudi I. et al.Age-related CD8 T cell clonal expansions constrict CD8 T cell repertoire and have the potential to impair immune defense.J. Exp. Med. 2004; 200: 1347-1358Crossref PubMed Scopus (199) Google Scholar]. In addition, CD28-null memory T cells tend to accumulate in the elderly, and these cells can generally suppress immune responses [63Goronzy J.J. et al.Value of immunological markers in predicting responsiveness to influenza vaccination in elderly individuals.J. Virol. 2001; 75: 12182-12187Crossref PubMed Scopus (361) Google Scholar, 64Saurwein-Teissl M. et al.Lack of antibody production following immunization in old age: association with CD8+CD28- T cell clonal expansions and an imbalance in the production of Th1 and Th2 cytokines.J. Immunol. 2002; 168: 5893-5899PubMed Google Scholar, 65Trzonkowski P. et al.Association between cytomegalovirus infection, enhanced proinflammatory response and low level of anti-hemagglutinins during the anti-influenza vaccination–an impact of immunosenescence.Vaccine. 2003; 21: 3826-3836Crossref PubMed Scopus (293) Google Scholar, 66Suciu-Foca N. et al.Generation and function of antigen-specific suppressor and regulatory T cells.Transpl. Immunol. 2003; 11: 235-244Crossref PubMed Scopus (101) Google Scholar]. However, the majority of memory cells in the aged individual are highly functional. Thus, in the face of the declining function of naive T cells with age, these observations reinforce the hypothesis that memory T cells dominate the cellular immune responses to newly encountered antigens in aged individuals. (iv) Memory T cells are more-readily activated than naive T cells. A fundamental characteristic of memory T cells is that their activation requirements are less stringent than those of naive T cells. This reduced requirement for co-stimulatory signals and accessory molecules enables memory T cells to respond to reduced antigen doses compared with naive cells [67Ahmed R. Gray D. Immunological memory and protective immunity: understanding their relation.Science. 1996; 272: 54-60Crossref PubMed Scopus (1481) Google Scholar, 68Dutton R.W. et al.The generation and maintenance of memory T and B cells.Immunol. Today. 1999; 20: 291-293Abstract Full Text Full Text PDF PubMed Scopus (33) Google Scholar, 69Seder R.A. Ahmed R. Similarities and differences in CD4+ and CD8+ effector and memory T cell generation.Nat. Immunol. 2003; 4: 835-842Crossref PubMed Scopus (688) Google Scholar]. Given the high level of cross-reactivity in the memory T-cell pool, these relaxed activation requirements would enable the triggering of relatively low-avidity cross-reactive memory T cells. We speculate that this provides an inherent bias towards the activation of cross-reactive memory cells from previous infections, particularly if the naive repertoire is compromised, as in aged animals. Considered together, these observations (Box 1) suggest that, as the numbers and function of the naive T cells decline with age, there are increasing numbers of potent memory T cells with the potential to cross-react with new pathogens. Thus, with increasing age, the immune response to newly encountered antigens might progressively be mediated by pre-existing memory T cells. Although it has been previously suggested that cross-reactive memory cells can modulate immune responses, we now extend this idea to suggest that the majority, if not all, of the response to newly encountered antigens in the elderly is mediated by these cells. Furthermore, the complete dependence on memory T cells to generate new responses might be reached as early as the age of 65, when homeostatic regulation of the naive T-cell pool seems to break down [21Naylor K. et al.The influence of age on T cell generation and TCR diversity.J. Immunol. 2005; 174: 7446-7452PubMed Google Scholar, 29Tanchot C. et al.Lymphocyte homeostasis.Semin. Immunol. 1997; 9: 331-337Crossref PubMed Scopus (131) Google Scholar, 30Surh C.D. Sprent J. Regulation of naive and memory T-cell homeostasis.Microbes Infect. 2002; 4: 51-56Crossref PubMed Scopus (67) Google Scholar].Hypothesis: cross-reactive memory T cells dominate responses to newly encountered pathogens in aged individuals• The T-cell recognition of antigen is degenerate and, therefore, highly cross-reactive. There is a high probability that memory cells will be able to recognize a newly encountered antigen.• The numbers and diversity of the naive T-cell pool decrease with age, resulting in the T-cell immune systems of the elderly consisting predominantly of memory cells. This increases the chance that the response to a new antigen will be mediated by fortuitously cross-reactive memory T cells.• Naive T cells, but not memory T cells, become functionally impaired with age. This further increases the chance that the response to a new antigen will be mediated by fortuitously cross-reactive memory T cells.• Memory T cells have lower activation and co-stimulatory requirements than naive T cells. Therefore, cross-reactive memory cells might compete effectively with aged naive T cells in the response to a newly encountered antigen.• Implications: de novo responses to new antigens will be mediated almost exclusively by cross-reactive memory T cells, leading to a highly stochastic response of reduced avidity, resulting in a compromised ability of the elderly to respond to new infections and vaccines. • The T-cell recognition of antigen is degenerate and, therefore, highly cross-reactive. There is a high probability that memory cells will be able to recognize a newly encountered antigen. • The numbers and diversity of the naive T-cell pool decrease with age, resulting in the T-cell immune systems of the elderly consisting predominantly of memory cells. This increases the chance that the response to a new antigen will be mediated by fortuitously cross-reactive memory T cells. • Naive T cells, but not memory T cells, become functionally impaired with age. This further increases the chance that the response to a new antigen will be mediated by fortuitously cross-reactive memory T cells. • Memory T cells have lower activation and co-stimulatory requirements than naive T cells. Therefore, cross-reactive memory cells might compete effectively with aged naive T cells in the response to a newly encountered antigen. • Implications: de novo responses to new antigens will be mediated almost exclusively by cross-reactive memory T cells, leading to a highly stochastic response of reduced avidity, resulting in a compromised ability of the elderly to respond to new infections and vaccines. The increasing dependence on cross-reactive memory cells in the aged would tend to result in weaker and delayed responses because T cells with lower avidity would tend to be drawn into the response [17Po J.L. et al.Age-associated decrease in virus-specific CD8+T lymphocytes during primary influenza infection.Mech. Ageing Dev. 2002; 123: 1167-1181Crossref PubMed Scopus (70) Google Scholar]. In addition, the dependence on cross-reactive memory cells would predict highly stochastic T-cell responses to new pathogens in the elderly, reflecting their previous antigen experience. The stochastic nature of the response would be further influenced by the individually unique clonal expansions of memory T cells that emerge with increasing age. Depending on the nature of the prior antigenic experience, the impact of persistent infections (e.g. EBV and CMV) [36Khan N. et al.Cytomegalovirus seropositivity drives the CD8 T cell repertoire toward greater clonality in healthy elderly individuals.J. Immunol. 2002; 169: 1984-1992PubMed Google Scholar], the distinct clonal expansions and the stochastic residual naive repertoire, the peripheral T-cell repertoire of an aged individual will be highly unique and extremely restricted. Indeed, there is a strong likelihood of 'holes' in the repertoire that might preclude the ability to generate a vigorous response to a new pathogen. In this regard, individual mice with large clonal expansions respond poorly to de novo herpes simplex virus-1 infection [62Messaoudi I. et al.Age-related CD8 T cell clonal expansions constrict CD8 T cell repertoire and have the potential to impair immune defense.J. Exp. Med. 2004; 200: 1347-1358Crossref PubMed Scopus (199) Google Scholar]. In addition, some individual aged H-2b mice that show no evidence of clonal expansions have highly skewed responses to de novo influenza virus infection (E. Yager, D. Woodland and M. Blackman, unpublished), and there are cases of selective loss of reactivity to the normally immunodominant nucleoprotein epitope, which elicits a restricted T-cell response [70Kedzierska K. et al.Conserved T cell receptor usage in primary and recall responses to an immunodominant influenza virus nucleoprotein epitope.Proc. Natl. Acad. Sci. U. S. A. 2004; 101: 4942-4947Crossref PubMed Scopus (127) Google Scholar]. Together, these age-associated constraints in the T-cell repertoire caused by reductions in naive T-cell numbers and the increasing reliance on fortuitously cross-reactive responses have significant implications for vaccination of the aged population. For example, vaccination strategies for the elderly should consider previous pathogen exposure, and should, perhaps, focus on boosting pre-existing memory T-cell responses. The age-associated decline in naive T-cell availability also highlights the importance of therapeutic approaches to improve the survival and maintenance of naive T cells, in addition to efforts to increase thymic output in the elderly [71Beverley P.C. Grubeck-Loebenstein B. Is immune senescence reversible?.Vaccine. 2000; 18: 1721-1724Crossref PubMed Scopus (32) Google Scholar, 72van den Brink M.R. et al.Strategies to enhance T-cell reconstitution in immunocompromised patients.Nat. Rev. Immunol. 2004; 4: 856-867Crossref PubMed Scopus (131) Google Scholar, 73Nikolich-Zugich J. T cell aging: naive but not young.J. Exp. Med. 2005; 201: 837-840Crossref PubMed Scopus (89) Google Scholar]. In conclusion, we hypothesize that the age-associated decline in the presence and function of naive T cells, and the resulting dominance of the repertoire by memory cells, restricts the de novo T-cell response to newly encountered pathogens to fortuitously cross-reactive memory cells, resulting in a severely compromised ability to respond to new infections and vaccines. Importantly, this hypothesis is directly testable in animal models, as are novel vaccination strategies for the elderly and therapeutic approaches for preserving the naive T-cell repertoire. We thank Laura Haynes for helpful discussions. This work was supported by grants from the NIH and funds from the Trudeau Institute.