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


Zhan, YF; Funda, DP; Every, AL; Fundova, P; Purton, JF; Liddicoat, DR; Cole, TJ; Godfrey, DI; Brady, JL; Mannering, SI; Harrison, LC; Lew, AM
2004-09
INTERNATIONAL IMMUNOLOGY
Journal Article
16
9
1315-1321
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.
OXFORD UNIV PRESS
THYMOCYTE DEVELOPMENT; GENE-EXPRESSION; RECEPTOR; CD4(+)CD25(+); APOPTOSIS; SELECTION; LYMPHOCYTES; THYMUS; LIGAND
10.1093/intimm/dxh134
Refer to copyright notice on published article.

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Creation Date 2004-09-01 12:00:00