A critical role for TNF receptor-associated factor 1 and Bim down-regulation in CD8 memory T cell survival.
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.
Sabbagh
Laurent
L
Department of Immunology, University of Toronto, 1 King's College Circle, Toronto, Ontario, Canada M5S 1A8.
Srokowski
Cathy C
CC
Pulle
Gayle
G
Snell
Laura M
LM
Sedgmen
Bradley J
BJ
Liu
Yuanqing
Y
Tsitsikov
Erdyni N
EN
Watts
Tania H
TH
D000818:Animals; D051017:Apoptosis Regulatory Proteins / Q000037:antagonists & inhibitors* / Q000096:biosynthesis / Q000235:genetics; D000072224:Bcl-2-Like Protein 11; D018414:CD8-Positive T-Lymphocytes / Q000166:cytology / Q000276:immunology*; D002470:Cell Survival / Q000235:genetics / Q000276:immunology; D007156:Immunologic Memory / Q000235:genetics; D008565:Membrane Proteins / Q000037:antagonists & inhibitors* / Q000096:biosynthesis / Q000235:genetics; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008822:Mice, Transgenic; D011518:Proto-Oncogene Proteins / Q000037:antagonists & inhibitors* / Q000096:biosynthesis / Q000235:genetics; D015398:Signal Transduction / Q000235:genetics / Q000276:immunology; D047990:TNF Receptor-Associated Factor 1 / Q000172:deficiency / Q000235:genetics / Q000502:physiology*
D051017:Apoptosis Regulatory Proteins; D000072224:Bcl-2-Like Protein 11; C000606776:Bcl2l11 protein, mouse; D008565:Membrane Proteins; D011518:Proto-Oncogene Proteins; D047990:TNF Receptor-Associated Factor 1