The process of activation-induced cell death (AICD) in T cells proceeds through a variety of mechanisms that engage different pathways of apoptotic cell death, involving on the one hand Bcl-2 family members that control the mitochondrial pathway of apoptosis, and on the other hand the death receptor-mediated apoptotic pathway. Our working hypothesis, forming a framework for the projects in this proposal, is that the different mechanisms of AICD combine in vivo to produce what we observe as peripheral T cell deletion, the clonal contraction of T cell numbers following initial expansion in response to antigen. In particular, our aims are to: 1. Compare potentially redundant modes of T cell autonomous AICD proceeding via restriction of survival signaling, and examine conditions under which they are engaged in immune homeostasis. We will explore the idea that if a T cell receives limited activation signals, the expansion and subsequent cell death that occur contributes to peripheral deletion of the population. We will test the role of a Bim-induced mitochondrial pathway in this phenomenon and explore how T cell """"""""programming"""""""" controls survival or cell death following activation. 2. Examine potentially redundant modes of T cell AICD that proceed via death ligand-receptor interactions, and examine conditions under which they are engaged in immune homeostasis. We will investigate T cell activation induced apoptosis mediated by death ligands, both where this is T cell autonomous and in the situation in which activated T cells induce nonlymphoid cells to express proteins that in turn kill the T cell. The former process will be analyzed in the context of TRAIL-mediated AICD that occurs when a CD8 T cell, primed in the absence of """"""""help"""""""" is restimulated. The latter process of """"""""inducible immune privilege"""""""" will be analyzed in terms of roles for the death ligand TRAIL in addition to FasL 3. Examine how glucose and AKT influence susceptibility to different pathways of AICD in an activated T cell. When a T cell is activated, survival signals are mediated by AKT/PKB. We will explore how AKT interferes with peripheral deletion and AICD, and will examine a pathway for AKT-mediated resistance to apoptosis. This pathway, involving GSK-3 and Hexokinase will be analyzed and test its roles in regulating the modes of AICD studied in the other aims. Our goals represent an integrated approach to understanding the processes of AICD and peripheral deletion and their relationships to the pathways of apoptosis.
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