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-x(L) 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-x(L) and ERK-dependent Bim down-modulation.

• Authors: Laurent Sabbagh, Gayle Pulle, Yuanqing Liu, Erdyni N Tsitsikov, Tania H Watts
• Journal: Journal of immunology (Baltimore, Md. : 1950) (J Immunol) Vol. 180 Issue 12 Pg. 8093-101 (Jun 15 2008) ISSN: 0022-1767 [Print] United States
• PMID: 18523273 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Apoptosis Regulatory Proteins
• Bcl-2-Like Protein 11
• Bcl2l1 protein, mouse
• Bcl2l11 protein, mouse
• Membrane Proteins
• Proto-Oncogene Proteins
• TNF Receptor-Associated Factor 1
• Tumor Necrosis Factor Receptor Superfamily, Member 9
• bcl-X Protein
• Extracellular Signal-Regulated MAP Kinases

Topics

• Animals
• Apoptosis (genetics, immunology)
• Apoptosis Regulatory Proteins (antagonists & inhibitors, physiology)
• Bcl-2-Like Protein 11
• CD8-Positive T-Lymphocytes (cytology, enzymology, immunology, virology)
• Cell Line, Tumor
• Cell Survival (genetics, immunology)
• Extracellular Signal-Regulated MAP Kinases (physiology)
• Lymphocyte Activation (genetics, immunology)
• MAP Kinase Signaling System (genetics, immunology)
• Membrane Proteins (antagonists & inhibitors, physiology)
• Mice
• Mice, Inbred C57BL
• Mice, Knockout
• Mice, Transgenic
• Orthomyxoviridae Infections (genetics, immunology)
• Proto-Oncogene Proteins (antagonists & inhibitors, physiology)
• TNF Receptor-Associated Factor 1 (deficiency, genetics, physiology)
• Tumor Necrosis Factor Receptor Superfamily, Member 9 (deficiency, genetics, physiology)
• bcl-X Protein (biosynthesis)