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T‐cell intrinsic effects of GITR and 4‐1BB during viral infection and cancer immunotherapy

Summary:  GITR [glucocorticoid inducible tumor necrosis factor receptor (TNFR)‐related protein] and 4‐1BB are costimulatory TNFR family members that are expressed on regulatory and effector T cells as well as on other cells of the immune system. Here we discuss the role of GITR and 4‐1BB on T cells during viral infections and in cancer immunotherapy. Systemic treatment with agonistic anti‐4‐1BB antibody leads to a number of immune system abnormalities, and clinical trials of anti‐4‐1BB have been terminated. However, other modes of 4‐1BB ligation may be less toxic. To date, similar toxicities have not been reported for anti‐GITR treatment of mice, although anti‐GITR antibodies can exacerbate mouse autoimmune models. Intrinsic effects of GITR and 4‐1BB on effector T cells appear to predominate over their effects on other cell types in some models. Despite their similarities in enhancing T‐cell survival, 4‐1BB and GITR are clearly not redundant, and both pathways are required for maximal CD8+ T‐cell responses and mouse survival following severe respiratory influenza infection. GITR uses TNFR‐associated factor (TRAF) 2 and TRAF5, whereas 4‐1BB recruits TRAF1 and TRAF2 to mediate survival signaling in T cells. The differential use of signaling adapters combined with their differential expression may explain the non‐redundant roles of GITR and 4‐1BB in the immune system.