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

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

Abstract

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.

Publication types

  • Research Support, Non-U.S. Gov't
  • Review

MeSH terms

  • Animals
  • Antibodies / administration & dosage
  • Antibodies / immunology*
  • Autoimmunity / drug effects
  • Cell Proliferation / drug effects
  • Gene Expression / immunology
  • Glucocorticoid-Induced TNFR-Related Protein / antagonists & inhibitors
  • Glucocorticoid-Induced TNFR-Related Protein / genetics
  • Glucocorticoid-Induced TNFR-Related Protein / immunology*
  • Glucocorticoid-Induced TNFR-Related Protein / metabolism
  • Humans
  • Immunity, Innate* / drug effects
  • Immunotherapy / methods
  • Influenza A virus / immunology
  • Mice
  • Mice, Knockout
  • Neoplasms / drug therapy
  • Neoplasms / immunology
  • Neoplasms / metabolism
  • Orthomyxoviridae Infections / immunology
  • Orthomyxoviridae Infections / virology
  • Signal Transduction / drug effects*
  • Signal Transduction / immunology*
  • T-Lymphocytes / drug effects
  • T-Lymphocytes / immunology*
  • T-Lymphocytes / metabolism
  • Tumor Necrosis Factor Receptor Superfamily, Member 9 / genetics
  • Tumor Necrosis Factor Receptor Superfamily, Member 9 / immunology*
  • Tumor Necrosis Factor Receptor Superfamily, Member 9 / metabolism
  • Tumor Necrosis Factor Receptor-Associated Peptides and Proteins / genetics
  • Tumor Necrosis Factor Receptor-Associated Peptides and Proteins / immunology*
  • Tumor Necrosis Factor Receptor-Associated Peptides and Proteins / metabolism

Substances

  • Antibodies
  • Glucocorticoid-Induced TNFR-Related Protein
  • Tnfrsf18 protein, mouse
  • Tumor Necrosis Factor Receptor Superfamily, Member 9
  • Tumor Necrosis Factor Receptor-Associated Peptides and Proteins