A critical role for TNF receptor-associated factor 1 and Bim down-regulation in CD8 memory T cell survival

Authors:
Sabbagh L, Srokowski CC, Pulle G, Snell LM, Sedgmen BJ, Liu Y, Tsitsikov EN, Watts TH
In:
Source: Proc Natl Acad Sci USA
Publication Date: (2006)
Issue: 103(49): 18703-8
Research Area:
Immunotherapy / Hematology
Cells used in publication:
T cell, mouse - C57BL/6
Species: mouse
Tissue Origin: blood
Platform:
Nucleofector® I/II/2b
Abstract
The mechanisms that allow the maintenance of immunological memory remain incompletely defined. Here we report that tumor necrosis factor receptor (TNFR)-associated factor (TRAF) 1, a protein recruited in response to several costimulatory TNFR family members, is required for maximal CD8 T cell responses to influenza virus in mice. Decreased recovery of CD8 T cells in vivo occurred under conditions where cell division was unimpaired. In vitro, TRAF1-deficient, antigen-activated T cells accumulated higher levels of the proapoptotic BH3-only family member Bim, particularly the most toxic isoform, Bim(S). In the presence of excess IL-15, memory phenotype T cells with similar surface phenotype and comparable levels of Bcl-2 family members could be generated from WT or TRAF1-deficient T cell receptor transgenic OT-I T cells. However, when the memory CD8 T cells were allowed to compete for survival signals in the absence of antigen in vivo, the TRAF1-deficient T cells showed decreased recovery compared with TRAF1-sufficient T cells. This defect in T cell recovery in vivo was alleviated by introduction of siRNA to down-modulate Bim in TRAF1-deficient memory T cells. These studies identify the TRAF1 signaling axis and Bim down-regulation as critical for CD8 memory T cell survival in vivo.