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* Department of Immunology, Medical Sciences Building, University of Toronto, Toronto, Ontario, Canada; and
Immune Disease Institute, Harvard Medical School, Boston, MA 02115
During an acute immune response, CD8 T cells undergo rapid expansion followed by a contraction phase during which the majority of activated T cells die, leaving a few survivors to persist as memory cells. The regulation of T cell survival is critical at each stage of this response. 4-1BB, a TNFR family member, has been implicated in prolonging the survival of activated and memory CD8 T cells; however, the precise mechanisms by which 4-1BB sustains T cell survival are incompletely understood. Upon aggregation on T cells, 4-1BB associates with two TNFR-associated factors (TRAF), TRAF1 and TRAF2. TRAF2 is essential for downstream signaling from 4-1BB; however, the role of TRAF1 in 4-1BB signaling has not been elucidated and there have been conflicting data as to whether TRAF1 provides a positive or a negative signal in T cells. In this study, we report that TRAF1 plays a critical role in survival signaling downstream of 4-1BB during CD8 T cell expansion in response to viral infection in vivo. Further analysis reveals that TRAF1-deficient cells are impaired in their ability to up-regulate the prosurvival Bcl-2 family member Bcl-xL and show increased levels of the proapoptotic Bcl-2 family member Bim following 4-1BB signaling. TRAF1-deficient CD8 T cells fail to activate ERK in response to 4-1BB ligation and inhibition of ERK signaling downstream of 4-1BB in wild-type cells leads to increased Bim levels. Thus, TRAF1 has a prosurvival effect in CD8 T cells via the 4-1BB-mediated up-regulation of Bcl-xL and ERK-dependent Bim down-modulation.
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1 This work was supported by Grant 015358 from the National Cancer Institute of Canada, with funds from the Canadian Cancer Society (to T.H.W.). L.S. is the recipient of a post-doctoral fellowship from the Fonds de la recherche en santé du Québec.
2 Address correspondence and reprint requests to Dr. Tania H. Watts, Department of Immunology, Room 5263 Medical Sciences Building, University of Toronto, Toronto, Ontario, M5S 1A8, Canada. E-mail address: tania.watts{at}utoronto.ca
3 Abbreviations used in this paper: TRAF, TNFR-associated factor; WT, wild type; HAU, hemagglutinin unit.
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