International Immunology Advance Access originally published online on July 19, 2004
International Immunology 2004 16(9):1315-1321; doi:10.1093/intimm/dxh134
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© 2004 The Japanese Society for Immunology
TCR-mediated activation promotes GITR upregulation in T cells and resistance to glucocorticoid-induced death
1 Walter & Eliza Hall Institute of Medical Research, 1G Royal Parade, Melbourne 3050, Australia
2 Division of Immunology and Gnotobiology, Institute of Microbiology, Czech Academy of Sciences, Vídenská 1083, 142 20, Prague 4, Czech Republic
3 Department of Biochemistry & Molecular Biology and 4 Department of Microbiology & Immunology, University of Melbourne, Royal Parade, Melbourne 3010, Australia
Correspondence to: A. M. Lew; E-mail: lew{at}wehi.edu.au
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.
Keywords: apoptosis, dexamethasone, GITR, glucocorticoid, T cell activation
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