Aging and IL-7-mediated CD8+ T Cell survival

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DESCRIPTION (provided by applicant): Age-associated changes occur in T cell immunity, contributing to increased risk of infection and malignancy. Probably, the most intriguing alteration in CD8+ T cell immunity with aging is memory CD8+ T cell expansion although the mechanism(s) and the consequences of this phenomenon are largely unknown. Recently, my lab investigated whether the age-associated expansion of memory CD8+ T cells was secondary to increased expression of IL-7 receptor alpha chain (IL-7Ra) which is critical for CD8+ T cell survival. In this study, cells expressing IL-7Ra high and low were found in a subset of memory cells called CD45RA+ effector memory (EMCD45RA+, CD45RA+ CCR7-) CD8+ T cells. In contrast to the expectation, the elderly (age ¿: 65) had expansion of IL-7Ra low EMCD45RA+ CD8+ T cells (25% of total CD8+ T cells) compared to the young (age ¿ 40). This finding raises several questions. How does such cell expansion occur? What is the immunologic consequence(s) of this cell expansion? The expansion of IL-7Ra low EMCD45RA+ CD8+ T cells could be secondary to chronic antigen stimulations by infections such as cytomegalovirus (CMV), which has been linked to the expansion of memory CD8+ T cells with aging. However, these cells poorly survive and proliferate in response to IL-7 and TCR triggering, respectively, indicating that neither IL-7 nor chronic TCR triggering alone is sufficient explanation for this phenomenon. Of interest, IL-7Ra low CD8+ T cells nicely proliferate and expand in response to IL-15 and a combination of IL-15 and TCR triggering, which suggests the role for IL-15 in expanding IL-7Ra low EMCD45RA+ CD8+ T cells. Thus, I hypothesize that IL-15 is critical for expanding IL-7Ra low EMCD45RA+ CD8+ T cells with aging via inducing antigen-independent (IL-15 alone) and -dependent (TCR triggering, possibly CMV, with IL-15) cell proliferation, and such expanded cells have altered functions. This hypothesis will be addressed with the following specific aims: 1) Investigate whether the expansion of IL-7Ra low EMCD45RA+ CD8+ T cells with aging is directly related to CMV infection; 2) Determine whether the expansion of IL-7Ra low EMCD45RA+ CD8+ T cells with aging steins from alterations in IL-15-mediated CD8+ T cell proliferation; and 3) Investigate whether expanded IL-7Ra low EMCD45RA+ CD8+ T cells in the elderly have altered function. The results of this study will advance our understanding about the effect of aging on the immune system, leading to better protection against infection and tumors.