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Department of Immunology, The Scripps Research Institute, La Jolla, CA 92037
The maintenance of T cell tolerance in the periphery proceeds through several mechanisms, including anergy, immuno-regulation, and deletion via apoptosis. We examined the mechanism underlying the induction of CD8 T cell peripheral tolerance to a self-Ag expressed on pancreatic islet β-cells. Following adoptive transfer, Ag-specific clone 4 T cells underwent deletion independently of extrinsic death receptors, including Fas, TNFR1, or TNFR2. Additional experiments revealed that the induction of clone 4 T cell apoptosis during peripheral tolerance occurred via an intrinsic death pathway that could be inhibited by overexpression of Bcl-2 or targeted deletion of the proapoptotic molecule, Bim, thereby resulting in accumulation of activated clone 4 T cells. Over-expression of Bcl-2 in clone 4 T cells promoted the development of effector function and insulitis whereas Bim–/– clone 4 cells were not autoaggressive. Examination of the upstream molecular mechanisms contributing to clone 4 T cell apoptosis revealed that it proceeded in a p53, E2F1, and E2F2-independent manner. Taken together, these data reveal that initiation of clone 4 T cell apoptosis during the induction of peripheral tolerance to a cross-presented self-Ag occurs through a Bcl-2-sensitive and at least partially Bim-dependent mechanism.
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1 This work was supported by National Institutes of Health Grants R01 DK50824 and T32 AI07606 (to L.A.S.), an Achievement Awards for College Scientists Foundation Fellowship (to W.L.R.), and a Juvenile Diabetes Research Foundation Fellowship (to C.-H.W.).
2 W.L.R. and C.-H.W. contributed equally to this work.
3 Current address: Earle A. Chiles Research Institute, Robert W. Franz Cancer Research Center, Providence Portland Medical Center, 4805 Northeast Glisan Street, Portland, OR 97213.
4 Current address: Therakos, 437 Creamery Way, Exton, PA 19341.
5 Address correspondence and reprint requests to Dr. Linda A. Sherman, The Scripps Research Institute, Department of Immunology IMM-15, 10550 North Torrey Pines Road, La Jolla, CA 92037. E-mail address: lsherman{at}scripps.edu
6 Abbreviations used in this paper: Tg, transgenic; HA, hemagglutinin; AICD, activation-induced cell death; LN, lymph node.
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