T-cell intrinsic effects of GITR and 4-1BB during viral infection and cancer immunotherapy.
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.
Department of Immunology, University of Toronto, Toronto, ON, Canada.
Laura M
LM
Snell
Gloria H Y
GH
Lin
Ann J
AJ
McPherson
Theo J
TJ
Moraes
Tania H
TH
Watts
D000818:Animals; D000906:Antibodies / Q000008:administration & dosage / Q000276:immunology*; D015551:Autoimmunity / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D015870:Gene Expression / Q000276:immunology; D053450:Glucocorticoid-Induced TNFR-Related Protein / Q000037:antagonists & inhibitors / Q000235:genetics / Q000276:immunology* / Q000378:metabolism; D006801:Humans; D007113:Immunity, Innate / Q000187:drug effects; D007167:Immunotherapy / Q000379:methods; D009980:Influenza A virus / Q000276:immunology; D051379:Mice; D018345:Mice, Knockout; D009369:Neoplasms / Q000188:drug therapy / Q000276:immunology / Q000378:metabolism; D009976:Orthomyxoviridae Infections / Q000276:immunology / Q000821:virology; D015398:Signal Transduction / Q000187:drug effects* / Q000276:immunology*; D013601:T-Lymphocytes / Q000187:drug effects / Q000276:immunology* / Q000378:metabolism; D053261:Tumor Necrosis Factor Receptor Superfamily, Member 9 / Q000235:genetics / Q000276:immunology* / Q000378:metabolism; D047988:Tumor Necrosis Factor Receptor-Associated Peptides and Proteins / Q000235:genetics / Q000276:immunology* / Q000378:metabolism
D000906:Antibodies; D053450:Glucocorticoid-Induced TNFR-Related Protein; C106544:Tnfrsf18 protein, mouse; D053261:Tumor Necrosis Factor Receptor Superfamily, Member 9; D047988:Tumor Necrosis Factor Receptor-Associated Peptides and Proteins