Send to

Choose Destination
Immunol Rev. 2011 Nov;244(1):197-217. doi: 10.1111/j.1600-065X.2011.01063.x.

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

Author information

Department of Immunology, University of Toronto, Toronto, ON, Canada.

Erratum in

  • Immunol Rev. 2012 Jan;245(1):265.


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.

[Indexed for MEDLINE]

Publication types, MeSH terms, Substances, Grant support

Supplemental Content

Full text links

Icon for Wiley
Loading ...
Support Center