Molecular alterations in the aging immune system

T he study of the developing immune system during fetal and early postnatal life has contributed substantially to the biological and molecular understanding of the immune response. At the other extreme of lifespan, the immune systems of aged animals and humans also undergo characteristic changes, often in the direction of apparently decreased immune competence. Aging-related changes have been widely recognized for some time, but many have defied cellular or molecular characterization. Recently, however, a number of findings have begun to elucidate the mechanisms underlying aging-related immune system changes. It has been widely observed that, with aging, substantial changes occur in both the functional and phenotypic profiles of T lymphocytes in humans and in experimental animal models. These changes include a shift toward greater proportions of CD4 + T cells of memory (CD44hiCD45RO +) phenotype and fewer cells of naive (CD441~ +) phenotype (1-5). Paralleling these phenotypic changes are functional changes that occur with aging, including decreased proliferation of T cells in response to TCRand costimulusmediated stimulation (1-3, 5-7) and alterations in the profiles of cytokines produced in response to T cell activation (2, 3, 5, 8). Aging-related changes in the early signal transduction events that occur in response to T cell stimulation have also been described (9-11). It has been suggested that some, but perhaps not all, of these changes in T cell responsiveness are the result of shifts from naive to memory T cell predominance with age. Zhou et al. (12) have pointed to a role for expression of fas in some changes that occur in T cells with age. Fas is a cell surface molecule that transduces signals which mediate apoptotic cell death (13). In their report, Zhou et al. demonstrate that expression of fas, as well as susceptibility to fasmediated cell death, is decreased in thymocytes and peripheral T cells of aged mice. To analyze the effect of fas expression, these investigators introduced a CD2-fas transgene, which reversed the age-dependent loss of fas and achieved sustained fas expression by T cells. Moreover, these investigators observed that expression of theJas transgene prevented a number of age-related T cell changes, including thymic involution, the shift toward a memory (CD44 hi) phenotype, the decrease in T cell proliferative response to anti-CD3 stimulation, and the altered cytokine profile of activated T cells. The mechanism by which fas mediates these effects is unclear. The authors observed that peripheral T cells infas transgenic mice do not undergo the usual age-related decrease in susceptibility to fas-mediated apoptosis, consistent with the hypothesis that fas-mediated apoptosis normally leads to elimination of less functional cells and, therefore, to maintenance of a more functional T cell population through cellular renewal. However, an equally striking observation by Zhou et al. is that Jas transgenic mice show decreased apoptosis of thymocytes in response to anti-CD3 cross-linking in vitro, suggesting that fas expression might actually protect some thymocyte subpopulations from apoptotic death. It wiU be of interest to further characterize the role of fas in the specific events that occur during T cell differentiation and in the course of immune responses, and to evaluate the effect of fas expression on other organ systems and on overall longevity. In addition, a critical issue recognized by Zhou et al. is the identification of the mechanism that underlies decreased fas expression with age. This issue is of interest both as a basic problem of gene regulation and expression, and in the context of its implications for intervening to prevent what may be the undesired consequences of diminished fas function. Recent results have also provided insights into the mechanisms underlying other long-observed changes that occur in the immune responsiveness of aged organisms. The in vivo antibody responses of aged rodents to T helper-dependent (TD) antigens are reduced in both titer and affinity when compared to the responses of young animals (14). The antigens studied have included a number of model proteins, among them viral or bacterial antigens relevant to clinical immunization (14, 15). Using idiotypic markers (16, 17) or in situ hybridization with VHand VL-spedfic probes (18, 19), it has recently been shown that the germline Ig repertoire used by B cells changes with age, although the mechanism(s) underlying these changes in V region usage have not been elucidated. The generation of high affinity TD Ab responses depends, not only on germline gene usage, but also on a unique mechanism of somatic hypermutation of the variable regions of heavy and light chain genes. Somatic mutation appears to occur during ongoing immune responses predominantly within germinal centers (GC), and is followed by the selective survival of those B cells that by chance express mutated Ig receptors with high affinity for the selecting antigen (20). Selective survival of B cells in this process appears to depend on a number of factors, including encounter of specific antigenand CD40-mediated interactions with T cells. After immunization, aged mice develop GC that have normal histologic architecture. Recently, however, it has been shown that somatic mutation fails to occur in the GC of aged