MECHANISMS OF STRESS-INDUCED APOPTOSIS IN T CELLS

La Jolla Inst For Allergy &Immunolgy, La Jolla CA

Investigators

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Abstract

DESCRIPTION (Adapted from Investigator's abstract): Apoptosis in lymphocytes represents a fundamental regulatory process for the immune system, and an understanding of that process has far-reaching implications for our understanding of normal homeostasis and immunological disease. While considerable progress has been made towards delineating the central mechanisms of apoptosis, little is known about the signal transduction events that trigger this phenomenon. This renewal application seeks to explore a new concept in apoptotic signaling, one that is based on our continuing progress in understanding the phenomenon of activation-induced apoptosis in T cell hybridomas. The investigator proposes to explore signals that are initiated by DNA damage and related stress in T cells, which culminate in the expression of members of the TNF family of ligands, including Fas-ligand (FasL). By analogy with activation-induced apoptosis, where TCR-mediated signals induce expression of FasL and subsequent interaction with Fas to induce cell death in a cell-autonomous fashion, he proposes that stress-induced signals activate FasL expression (and probably that of related apoptosis-inducing ligands) through engaging the Jun-kinase pathway (to activate AP-1) and the activation of NF-kB. His two major aims in this project are 1) to dissect the signaling events that connect stress to FasL expression and subsequent apoptosis in T cells, and 2) to determine which of the TNF-family ligands (in addition to FasL) participate in stress-induced apoptosis in these cells. T lymphocytes utilize autocrine growth factor/receptor expression as a route to entry into the cell cycle following activation, by inducing transcription of DNA synthesis machinery, and the same general principle appears to apply to autocrine death-inducing ligands which interact with their receptors to trigger apoptosis via activation of the caspase proteases. This is a powerful concept, and the investigator will analyze the activation of the FasL promoter under conditions of stress to evaluate the roles of AP-1, NF-kB, c-Myc, and other relevant transcription factors, and he will compare and contrast these with the events associated with activation-induced FasL transcription (which appear to be different). It is anticipated that results generated in T cells may be relevant to some nonlymphoid systems as well. His focus on T lymphocytes is important in the context of understanding how the immune system responds to DNA damage and related stress to remove potentially damaged cells, that could otherwise pose a threat to immune integrity.