The tumor necrosis factor receptor family member 4-1BB plays a key role in the survival of activated and memory CD8(+) T cells. Depending on the disease model, 4-1BB can participate at different stages and influence different aspects of the immune response, likely due to the differential expression of receptor and ligand relative to other costimulatory molecules. Studies comparing mild versus severe influenza infection of mice suggest that the immune system uses inducible receptors such as 4-1BB to prolong the immune response when pathogens take longer to clear. The expression of 4-1BB on diverse cell types, evidence for bidirectional as well as receptor-independent signaling by 4-1BBL, the unexpected hyperproliferation of 4-1BB-deficient T cells, and complex effects of agonistic anti-4-1BB therapy have revealed additional roles for the 4-1BB/4-1BBL receptor/ligand pair in the immune system. In this review, we discuss these diverse roles of 4-1BB and its ligand in the immune response, exploring possible mechanisms for the observed complexities and implications for therapeutic applications of 4-1BB/4-1BBL.

Material Supplementary 2.DC1http://www.jimmunol.org/content/suppl/2010/11/12/jimmunol.100191References

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.

Background: The T cell costimulatory molecule 4-1BB signals through TRAF1 and TRAF2. Results: TRAF1Ϫ/Ϫ T cells show hyperproliferation due to enhanced alternative NF-B activation but have impaired classical

Immunity to viruses must be tightly controlled to avoid pathology. Receptors and ligands of the tumor necrosis factor (TNF) family play important roles in controlling lymphocyte activation and survival during an immune response. The role of specific TNF receptor (TNFR) family members in antiviral immunity depends on the stage of the immune response and can vary with the virus type and its virulence. Here, we focus on five members of the TNFR family that are prominently expressed on CD8(+) T cells during viral infections, namely, 4-1BB (CD137), CD27, OX40 (CD134), GITR, and TNFR2. 4-1BB, CD27, OX40, and GITR have primarily prosurvival roles for CD8(+) T cells during viral infection, although under some circumstances 4-1BB, GITR, or CD27 signals can limit immunity. Although TNFR2 can be costimulatory under some circumstances, its main role in CD8(+) T-cell responses during viral infection appears to be in contraction of the response. Several TNF family ligands are being explored as adjuvants for viral vaccines, and agonistic antibodies to TNFR family members are being investigated for immunotherapy of chronic viral infection alone and in combination with checkpoint blockade. Such therapies will require thorough and specific optimization to avoid pathology induced by hyperstimulation of these pathways.