It has been repeatedly demonstrated that aging is associated with a decreased immune response. Although the changes that have been reported to occur in immune responses with increasing age are varied, the number of studies addressing the changes that occur specifically in response to viral infection are limited. In general the virus-associated studies indicate that, relative to young subjects, aged subjects demonstrate: 1) a decreased proliferative response and decreased cytotoxic T cell response; 2) altered patterns of cytokine production and altered cell origins of the cytokines; and 3) altered apoptosis of antigen stimulated cells at the peak of the response. Our recent data further indicates that the depletion of non-specific T cells that occurs at the initiation of some virus infections does not occur in aged mice. Further, while the mechanism(s) of the decreased responses have not been definitively established in any system, it is becoming apparent that the decreased T cell response of aged mice reflects both changes intrinsic to the T cells and changes in the environment, with the latter reflecting both changes in antigen presenting cells and in cytokines produced by non-T cells. Our data in the E55+MuLV system indicate that the decreased immune response to a primary virus challenge reflects multiple levels of age-related changes resulting in both a decrease and a delay in virus specific responses and associated delay in viral clearance. We hypothesize that limited depletion of nonspecific T cells early during virus infections is a major contributor to the decreased immune response of the elderly. This limited depletion is due to age-associated changes both extrinsic and intrinsic to T cells. Based on this hypothesis, the study has two specific aims: 1) To definitively establish that the age-associated resistance of T cells to depletion early during infection with E55+MuLV is reflective of age-associated changes in response to primary virus infections that are general in nature by examining three virus systems in mice of two different genetic backgrounds. 2) To explore mechanisms of this age-associated change in depletion of non-specific T cells early after virus infection focusing on a) IFN-I and TNF-alpha as extrinsic factors, and b) induction of apoptosis in T cells as an intrinsic modification. These studies should provide information regarding the altered immune response with age that is essential for development of strategies to augment the immune response in aged individuals.
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