DESCRIPTION(provided by applicant): Aging of the immune system has significant impact on morbidity and survival. In the elderly, the incidence of severe infection increases and the protective factor of vaccination wanes. In this proposal, we hypothesize that cellular senescence of CD4+ and CD8+ memory T cells contributes to the decline of protective immunity in the aging individual and is in part responsible for the reactivation of chronic viral infections. Memory T cells are under high replicative stress from both antigen-specific and homeostatic proliferation. Progressive telomere shortening, changes in cell cycle kinetics, and resistance to apoptosis-inducing stimuli are all consistent with the model that memory cells undergo cellular senescence. Cellular senescence is associated with changes in gene expression. The most widely appreciated change is the loss of the costimulatory molecule, CD28. However, the senescence program also causes aberrant expression of genes, including the killer immunoglobulin-like receptors (KIRs) and other functionally related genes encoded in the leukocyte receptor complex. Many of these genes encode for inhibitory regulatory molecules that may dampen T-cell responses to antigen and may synergize with the loss of CD28. We hypothesize that immune function in the elderly is compromised by this gain in gene expression. This model is consistent with the evolutionary theory of antagonistic pleiotropy, which implies that genes selected to enhance the fitness of young organisms have unselected deleterious effects in the aging organism. We will test this hypothesis in models of chronic herpes virus infection. In Specific Aim #1, we propose to analyze the age-dependency of the expression of inhibitory KIRs in CMV- and EBV-specific CD8+ T cells. The functional relevance of KIR expression on antigen-specific CD8 + T-cell responses will be tested in vitro and in the in vivo system of the EBV-associated lymphoproliferative disorder in Specific Aim #2. Parallel studies will be performed with antigen-specific CD4+ T cells in Specific Aim #3. In Specific Aim #4, the effect of CD4 + and CD8 + senescent T cells on dendritic cell function will be analyzed to test the hypothesis that gene expression in senescent T cells also has a direct effect on the microenvironment of antigen-presenting cells. The clinical relevance of these hypotheses will be tested in Specific Aim #5. Biomarkers indicative of T cell senescence, including the expression of inhibitory KIRs, will be analyzed for their prognostic value to identify healthy elderly patients who are at risk of herpes zoster reactivation. Finally, in Specific Aim #6, we will examine the transcriptional control of KIR expression to test the hypothesis that expression in senescent T cells is a default to a developmental pathway characteristic of natural killer cells. This proposal takes a novel view on the phenomenon of immunosenescence. Instead of considering immunosenescence as an acquired immune defect, we propose that active immune mechanisms and immune defects act in concert. The promise of this concept is that targeting these active mechanisms can, in part, restore immunocompetence.
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