title: TCR-mediated activation promotes GITR upregulation in T cells and resistance to glucocorticoid-induced death.
abstract: 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.
authors.affiliation: Walter & Eliza Hall Institute of Medical Research, 1G Royal Parade, Melbourne 3050, Australia.
authors.forename: Yifan
authors.initials: Y
authors.lastname: Zhan
authors.forename: David P
authors.initials: DP
authors.lastname: Funda
authors.forename: Alison L
authors.initials: AL
authors.lastname: Every
authors.forename: Petra
authors.initials: P
authors.lastname: Fundova
authors.forename: Jared F
authors.initials: JF
authors.lastname: Purton
authors.forename: Douglas R
authors.initials: DR
authors.lastname: Liddicoat
authors.forename: Timothy J
authors.initials: TJ
authors.lastname: Cole
authors.forename: Dale I
authors.initials: DI
authors.lastname: Godfrey
authors.forename: Jamie L
authors.initials: JL
authors.lastname: Brady
authors.forename: Stuart I
authors.initials: SI
authors.lastname: Mannering
authors.forename: Leonard C
authors.initials: LC
authors.lastname: Harrison
authors.forename: Andrew M
authors.initials: AM
authors.lastname: Lew
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects*; D017252:CD3 Complex / Q000276:immunology; D016207:Cytokines / Q000096:biosynthesis; D003907:Dexamethasone / Q000494:pharmacology; D053450:Glucocorticoid-Induced TNFR-Related Protein; D008213:Lymphocyte Activation; D051379:Mice; D008810:Mice, Inbred C57BL; D011948:Receptors, Antigen, T-Cell / Q000502:physiology*; D011965:Receptors, Glucocorticoid / Q000502:physiology; D017475:Receptors, Nerve Growth Factor / Q000096:biosynthesis*; D018124:Receptors, Tumor Necrosis Factor / Q000096:biosynthesis*; D013601:T-Lymphocytes / Q000276:immunology*
chemical_list: D017252:CD3 Complex; D016207:Cytokines; D053450:Glucocorticoid-Induced TNFR-Related Protein; D011948:Receptors, Antigen, T-Cell; D011965:Receptors, Glucocorticoid; D017475:Receptors, Nerve Growth Factor; D018124:Receptors, Tumor Necrosis Factor; C106544:Tnfrsf18 protein, mouse; D003907:Dexamethasone