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. In vitro experiments have suggested that the cellular defect resembles that of cytokine unresponsiveness, and detailed studies of IL-2 and IL-15 signaling in these transgenic mice are underway in collaboration with members of Dr. O'shea's group. Genetic crosses to test the role of IL-15 and Stat-5 in this phenomenon are underway with Dr. Tagaya's and Dr. Leonard's groups, respectively. Testing of the competency of v-FLIP expressing CD8 T cells to mature into effector and memory cells in response to an infectious challenge (Influenza PR8 strain) will be studied, as well as the competency of v-FLIP transgenic T cells in CD4-mediated (EAU, Dr. Caspi) and CD8-mediated Diabetes (RIP-Ova recipients of OT-1 Ova-specific T cells, Drs. Picirrilo and Shevach) are being studied. 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.

Project Start
Project End
Budget Start
Budget End
Support Year
1
Fiscal Year
2002
Total Cost
Indirect Cost
Name
Arthritis, Musculoskeletal, Skin Dis
Department
Type
DUNS #
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State
Country
United States
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