Glucocorticoid/Stress Effects on Dendritic Cell Function

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There is substantial evidence for psychological stress-induced, neuroendocrine-mediated modulation of mmune function. The long-range goal of this program is to define the cellular and molecular mechanisms by which psychological stress and its associated increase in corticosterone affect CD8+ cytotoxic T lymphocyte (CTL) responses. An efficient and robust CD8+ CTL lymphocyte response is necessary for the successful defense against many diseases that are immunologically resisted, in particular, virus infections and some tumors. The efficiency and robustness of this response is absolutely dependent upon the efficient functioning of dendritic cells. Dendritic cells must process and present sufficient antigen at the right time and in the right place for successful activation of CD8+ T cells. Any impairment of these critical functions will undermine CD8+ T cell responses. Thus, an understanding of stress/corticosterone-mediated suppression of CD8+ T cell immunity is incomplete without an understanding of the effects of stress/corticosterone on dendritic cells. Knowledge of the cellular and molecular processes involved in antigen processing and presentation and dendritic cell function provide a unique opportunity to dissect the mechanisms underlying stress-associated regulation of immune function. Therefore, our current objective is to use this knowledge to test the hypothesis that stress and stress-associated increases in corticosterone modulate dendritic cell function. Specifically, we address those functions associated with dendritic cell maturation, and the ability of dendritic cells to process and present MHC class l-restricted antigen and induce antigen-specific CTL. These studies specifically focus on both direct- and cross-presentation pathways of antigen presentation and on the activation and maturation of dendritic cells that are required to ensure a protective CTL response. To achieve this objective, three specific aims are proposed: (I) To determine the sub-cellular mechanism of action of corticosterone on the direct pathway of MHC class I antigen processing and presentation; (II) To determine the effect of glucocorticoids and stress on cross-presentation in vitro and in vivo and; (III) To determine the effect of glucocorticoids and stress on dendritic cell maturation and function in vitro and in vivo. The rationale for the proposed research is that an understanding of the impact of corticosterone and stress on dendritic cell antigen presentation and maturation is a critical link to understanding the mechanisms by which stress-induced glucocorticoids influence the development of naturally-derived immunity and immunity that is elicited by vaccination. At the completion of this project we will expect to have identified those components of crucial dendritic cell functions that are affected by stress and glucocorticoids and the resulting impact on the generation of CD8+ CTL responses.