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

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.

Lipoxin A4 impairment of apoptotic signaling in macrophages: implication of the PI3K/Akt and the ERK/Nrf-2 defense pathways

“…Incubation of macrophages with staurosporine induces a rapid activation of JNK and p38 MAPKs, but not of ERK, a classic survival pathway. 36 Interestingly, pretreatment with LX was able to promote ERK phosphorylation in the presence of staurosporine without affecting either JNK or p38 activities. Furthermore, MAPK pathway associates with the modulation of antioxidant response element (ARE)-driven gene expression through Nrf-2 activation, a transcription factor that is considered as the 'guardian of redox homeostasis'.…”

TNF Receptor-Associated Factor (TRAF) Signaling Network in CD4⁺ T-Lymphocytes

“…This ERK activation promotes CD8 + T-cell survival through downregulation of the proapoptotic molecule Bim (Wang et al 2007;Sabbagh et al 2008). Upon 4-1BB triggering, TRAF1 associates with leukocyte-specific protein 1 (LSP1) in activated CD8 + T cells, and the TRAF1-LSP1 complex is essential for the 4-1BB-dependent ERK activation (Sabbagh et al 2013).…”

“…Traf1 −/− memory CD8 + T cells cannot efficiently control the lymphocytic choriomeningitis virus (LCMV) in chronic stages of infection ). TRAF1 exhibits a prosurvival effect in CD8 + T cells via 4-1BB-mediated upregulation of the prosurvival Bcl-x L and 4-1BB-ERK-dependent downregulation of the proapoptotic Bim (Sabbagh et al 2008). These results demonstrate that the 4-1BB-TRAF1 signaling is critical for the effector function and long-term survival of antigen-primed CD8 + T cells.…”

“…4-1BB-mediated activation of ERK is severely impaired in Traf1 −/− CD8 + T cells (Sabbagh et al 2008). This ERK activation promotes CD8 + T-cell survival through downregulation of the proapoptotic molecule Bim (Wang et al 2007;Sabbagh et al 2008).…”

Contribution of 4–1BBL on radioresistant cells in providing survival signals through 4–1BB expressed on CD8+ memory T cells in the bone marrow

“…Previous results using adoptive transfer of in vitro generated OT-I memory T cells into unimmunized mice revealed a two-to threefold defect in their maintenance after 3 weeks in 4-1BBL-deficient mice, under conditions where there was no defect in cell division [29]. 4-1BB engagement provides a survival signal to CD8 + effector and memory T cells that involves the TRAF1-dependent downmodulation of Bim [30,31]. However, the cells that contribute 4-1BBL to the CD8 + memory T cells have not been identified.…”