The 'death receptor' subfamily of TNF receptors is known to mediated programmed cell death through recruitment of caspases to a death domainin 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. Although elimination of the death receptor Fas/CD95 results in autoimmunity through blocking elimination of autoreactive T cand B cells, 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 effexts of blocking apoptosis signaling at various levels on autoimmune disease models.
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