ERK-Dependent Bim Modulation Downstream of the 4-1BB-TRAF1 Signaling Axis Is a Critical Mediator of CD8 T Cell Survival In Vivo

• DOI: 10.4049/jimmunol.180.12.8093
• Publication Date: 2014-04-18T23:24:59Z
• Authors: Laurent Sabbagh; Gayle Pulle; Yuanqing Liu; Erdyni N Tsitsikov; Tania H Watts
• Keywords: Mice, Knockout; Bcl-2-Like Protein 11; Cell Survival; MAP Kinase Signaling System; bcl-X Protein; Membrane Proteins; Apoptosis; Mice, Transgenic; CD8-Positive T-Lymphocytes; Lymphocyte Activation; TNF Receptor-Associated Factor 1; 3. Good health; Mice, Inbred C57BL; Mice; Tumor Necrosis Factor Receptor Superfamily, Member 9; 03 medical and health sciences; 0302 clinical medicine; Orthomyxoviridae Infections; Cell Line, Tumor; Proto-Oncogene Proteins; Animals; Apoptosis Regulatory Proteins; Extracellular Signal-Regulated MAP Kinases

Abstract 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.