Role of 4-1BBL and TRAF1 in the CD8 T Cell Response to Influenza Virus and HIV
4-1BB is an inducible member of the TNFR family found on antigen-activated T cells as well as on cells of the innate immune system. 4-1BB is a late-acting survival factor for effector T cells, sustaining CD8 T cell survival in the lung during severe respiratory infection with influenza virus. With milder influenza infections, 4-1BBL is dispensable for initial CD8 T cell responses. However, 4-1BB on the CD8 T cells and 4-1BBL primarily on radioresistant cells are important in maintaining CD8 T cell memory to influenza virus. 4-1BB is induced on memory but not naive CD8 T cells independently of antigen, by common gamma chain cytokines such as IL-15 and IL-2. This allows memory CD8 T cells to respond to 4-1BBL in the absence of antigen. 4-1BB transduces signals via recruitment of TRAF1 and TRAF2. Earlier work had shown that TRAF2 was essential for 4-1BB signaling in T cells, whereas the role of TRAF1 was unclear. Our recent studies have demonstrated the importance of TRAF1 in the survival of activated and memory CD8 T cells. We also showed that 4-1BB and TRAF1 are important in the costimulation-dependent rescue of functional CD8 T cells from a starting population of non-functional HIV-specific T cells isolated from chronically infected individuals. Downstream of 4-1BB, TRAF1 maintains the stability of TRAF2 and allows ERK-dependent depletion of the proapoptotic molecule BIM, resulting in increased CD8 T survival. Recently several reports have identified linkages between autoimmunity and single nucleotide polymorphisms in the TRAF1/C5 region. Further work is required to determine whether specific polymorphisms in TRAF1 could influence the ability of different individuals to respond to infection.
Funding for our research is provided by the Canadian Institutes of Health Research (CIHR) and the Canadian Cancer Society. G.H.Y. Lin is funded by a CIHR studentship; L.M. Snell is funded by the Fonds de la recherche en santé Quebec; C. Wang is funded by an Ontario HIV treatment network studentship; and L. Sabbagh, by a fellowship from the Leukemia and Lymphoma Society of America. T.H.W. holds the sanofi pasteur chair in Human Immunology at the University of Toronto.
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