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

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

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.

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.

Loss of intracellular TRAF1 expression correlates with CD8+ T cell exhaustion and contributes to increased viral load at the chronic stage of HIV and LCMV infection, a phenotype that can be reversed by IL-7 stimulation together with 4-1BB agonist.

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Several members of the tumor necrosis factor receptor family regulate T cell expansion by influencing T cell activation and survival. Among these, glucocorticoid-induced TNF receptor family-related gene (GITR) is of interest, as it is expressed on both effector and regulatory T cells. While much work has focused on the role of GITR on regulatory T cells, little is known about its role on effector T cells in an infectious disease context. We sought, therefore, to examine the intrinsic role of GITR on CD8 T cells during a viral infection. To do this, we employed an adoptive transfer model where WT and GITR-/- TCR transgenic OT-I CD8 T cells were forced to compete with each other in response to infection with a recombinant influenza virus carrying the ovalbumin epitope recognized by OT-I, Influenza A/X31-OVA. In both the primary and secondary response to virus profound defects in GITR-/- OT-I T cell numbers were detected in all organs examined. Further investigation revealed that the decreased number of GITR-/- OT-I T cells was not due to a homing or proliferative defect, but rather that GITR was important for TRAF2 and TRAF5 mediated T cell survival signaling. Moreover, we also used a similar adoptive transfer model to show that GITR is required on CD8 T cells for enhancement of influenza-specific CD8 T cell expansion upon administration of agonistic anti-GITR antibody. These results highlight the importance of GITR as a CD8 T cell costimulator during acute viral infection.