GITR, a member of the TNF receptor superfamily, is costimulatory to mouse T lymphocyte subpopulations

Eur J Immunol. 2004 Mar;34(3):613-622. doi: 10.1002/eji.200324804.


GITR (glucocorticoid-induced TNFR family related gene) is a member of the TNFR superfamily (TNFRSF) that is expressed in different cell types, including T lymphocytes. Because of a high homology in its cytoplasmic region with other known costimulatory members of the TNFRSF, we investigated whether GITR played a costimulatory role in T lymphocyte subpopulations. Our results show that the proliferation response of CD8+ and CD4+ peripheral T cell subpopulations was potentiated when a GITR costimulus was added to an anti-CD3 stimulus. Furthermore, expression of the main activation-induced receptor (IL-2Ralpha) and production of IL-2 and IFN-gamma were increased more with a GITR costimulus than with anti-CD3 alone. GITR stimulation also enhanced anti-CD3-induced ERK phosphorylation, suggesting that GITR is involved in MAPK-pathway activation. Interestingly, CD4+CD25+ regulatory T cell (Treg cell) proliferation was triggered by the GITR costimulus; Treg cell proliferation was paralleled by the loss of the anergic phenotype and suppressor activity. Nevertheless, unstimulated GITR(-/-) CD4+CD25+ and GITR(+/+) CD4+CD25+ cells were equally able to exert suppressor activity on CD4+CD25- responder cells. These results indicate a novel function for GITR as costimulatory molecule of T cell subsets.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Antibodies / pharmacology
  • Apoptosis
  • CD3 Complex / immunology
  • CD4-Positive T-Lymphocytes / immunology
  • Cells, Cultured
  • Cytokines / metabolism
  • Glucocorticoid-Induced TNFR-Related Protein
  • Lymphocyte Activation*
  • Mice
  • Mice, Knockout
  • Receptors, Interleukin-2 / analysis
  • Receptors, Nerve Growth Factor / genetics
  • Receptors, Nerve Growth Factor / immunology
  • Receptors, Nerve Growth Factor / physiology*
  • Receptors, Tumor Necrosis Factor / genetics
  • Receptors, Tumor Necrosis Factor / immunology
  • Receptors, Tumor Necrosis Factor / physiology*
  • Signal Transduction
  • T-Lymphocyte Subsets / immunology*


  • Antibodies
  • CD3 Complex
  • Cytokines
  • Glucocorticoid-Induced TNFR-Related Protein
  • Receptors, Interleukin-2
  • Receptors, Nerve Growth Factor
  • Receptors, Tumor Necrosis Factor
  • Tnfrsf18 protein, mouse