TCR-mediated activation promotes GITR upregulation in T cells and resistance to glucocorticoid-induced death

Int Immunol. 2004 Sep;16(9):1315-21. doi: 10.1093/intimm/dxh134. Epub 2004 Jul 19.


T lymphocytes (pivotal in many inflammatory pathologies) are targets for glucocorticoid hormone (GC). How TCR-mediated activation and GC signaling via glucocorticoid receptor (GR) impact on T-cell fates is not fully defined. We delineated here the expression of a recently identified glucocorticoid-induced TNF receptor (GITR) induced by GC and by TCR-mediated T-cell activation in GC receptor (GR)-deficient mice (GR-/-). We also compared the action of GC on GITR+ and GITR- T cells by monitoring apoptosis, proliferation and cytokine production stimulated by anti-CD3 antibody. By using GR-/- mice, we observed that the development of GITR+ T cells (both in thymus and periphery) is not dependent upon GR signaling. This contradicts the implication of GITR's name reflecting GC induction. TCR-mediated T-cell activation induced GITR expression in both GR+/+ and GR-/- cells. Somewhat unexpectedly, there was very modest GITR upregulation on GR+/+ T cells by a range of GC doses (10(-8) to 10(-6) M). Constitutive expression of GITR by a subset of CD4+ cells did not significantly render them resistant to GC-induced cell death. However, TCR-induced GITR upregulation on GR+/+ T cells was correlated with resistance to GC-mediated apoptosis suggesting that GITR, in conjunction with other (as yet unidentified) TCR-induced factors, protects T cells from apoptosis. Thus, even though GC is a potent inducer of apoptosis of T cells, activated T cells are resistant to GC-mediated killing. Meanwhile, although GC suppressed anti-CD3-induced cytokine production, cell proliferation was unaffected by GC in GR+/+ mice. GR deficiency has no effect on anti-CD3-induced cytokine production and proliferation. Our findings also have implications for GC treatment in that it would be more difficult to abrogate an ongoing T-cell mediated inflammatory response than to prevent its induction.

Publication types

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

MeSH terms

  • Animals
  • Apoptosis / drug effects*
  • CD3 Complex / immunology
  • Cytokines / biosynthesis
  • Dexamethasone / pharmacology
  • Glucocorticoid-Induced TNFR-Related Protein
  • Lymphocyte Activation*
  • Mice
  • Mice, Inbred C57BL
  • Receptors, Antigen, T-Cell / physiology*
  • Receptors, Glucocorticoid / physiology
  • Receptors, Nerve Growth Factor / biosynthesis*
  • Receptors, Tumor Necrosis Factor / biosynthesis*
  • T-Lymphocytes / immunology*


  • CD3 Complex
  • Cytokines
  • Glucocorticoid-Induced TNFR-Related Protein
  • Receptors, Antigen, T-Cell
  • Receptors, Glucocorticoid
  • Receptors, Nerve Growth Factor
  • Receptors, Tumor Necrosis Factor
  • Tnfrsf18 protein, mouse
  • Dexamethasone