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.