Ligands and receptors in the Tumor Necrosis Factor (TNF) superfamily exert important modifying effects on innate and adaptive immune responses. The 'death receptor' subfamily of TNF receptors is known to mediated programmed cell death through recruitment of caspases to the intracellular tail of the receptor. In the immune system, signaling through death receptors eliminates autoreactive T and B cells at a number of critical checkpoints in peripheral differentiation. Elimination of the death receptor Fas/CD95 results in autoimmunity through blocking elimination of autoreactive T and B cells. However, recent experimental evidence suggests that the adapter protein FADD and the initiator caspase-8 enzyme can also mediate some aspects of T cell activation. To study the cell-type specific function of death receptor signaling, we have generated transgenic mice overexpressing v-FLIP, a potent viral blocker of death receptor signal transduction. In T-cell specific CD2-vFLIP transgenic mice, decreased Fas-mediated apoptosis was seen, but more prominently, a defect in post-activation T cell survival was seen in vitro and in vivo, resulting in a severe deficit of memory phenotype peripheral CD8 T cells. The long-term goals of this study are to better understand the cross-talk between apoptosis and survival signaling pathways in various lymphocyte subsets, and study the effects of blocking apoptosis signaling at various levels on autoimmune disease models. In the past year, we have identified a clear molecular defect in response of activated vFLIP cells to cytokines that signal through the common gamma chain (for example, IL-2, 7 and 15). We are now working on defining the mechanism by which these cells are unable to respond to growth and survival promoting cytokines. These experiments are designed to reveal how the signaling pathways mediating death-receptor induced apoptosis and cytokine mediated cellular survival interact. We have also begun studies on the role of interactions between the TNF-family ligand TL1A and the receptor DR3 in immune cell activation and homeostasis. DR3 is a death-domain containing receptor expressed primarily on lymphocytes. This receptor has been shown to be involved in negative selection of autoreactive thymocytes, but its role in peripheral immune homeostasis has not been defined. We have discovered that rather than being solely expressed in endothelial cells. TL1A, the DR3 ligand, is induced in myeloid cells during T cell activation and therefore is poised to function as a T cell response modifier. Preliminary evidence suggests that endogenously expressed TL1A may function as a negative regulator of T cell proliferation. Experiments are underway with TL1A blocking reagents and DR3 knockout mice to more clearly define the role of this receptor-ligand pair in normal and autoimmune T cell responses.
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