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c-FLIP Protects Mature T Lymphocytes from TCR-Mediated Killing¹

Department of Immunology, Duke University Medical Center, Durham, NC 27710

Although c-FLIP has been identified as an important player in the extrinsic (death receptor-induced) apoptosis pathway, its endogenous function in mature T lymphocytes remains undefined. c-FLIP may inhibit or promote T cell death as previous data demonstrate that the c-FLIP_L isoform can promote or inhibit caspase 8 activation while the c-FLIP_S isoform promotes or inhibits T cell death when overexpressed. Although the c-FLIP_R isoform inhibits cell death in cell lines, its function in T cells remains unknown. To investigate the function of c-FLIP in mature T cells, we have generated several genetic mouse models with c-FLIP or its individual isoforms deleted in mature T cells. Surprisingly, we found that c-FLIP protects mature T cells not only from apoptosis induced by the death receptors Fas and TNFR but also from TCR-mediated and spontaneous apoptosis. Thus, c-FLIP plays an essential role in protecting mature T cells from a death signal induced through the TCR itself and is required for naive T cell survival. Our results demonstrate that c-FLIP functions beyond the extrinsic death pathway.

The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ This work was supported by National Institutes of Health Grants CA92123 and AI54683.

² Address correspondence and reprint requests to Dr. You-Wen He, Box 3010, Department of Immunology, Duke University Medical Center, Durham, NC 27710. E-mail address: he000004{at}mc.duke.edu

³ Abbreviations used in this paper: Tg, transgenic; BAC, bacterial artificial chromosome; LN, lymph node; zVAD, benzyloxycarbonyl-Val-Ala-Asp.

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