title: CD28 regulates glucocorticoid-induced TNF receptor family-related gene expression on CD4+ T cells via IL-2-dependent mechanisms.
abstract: The glucocorticoid-induced TNF-related gene receptor (GITR) is the newest member of the costimulatory molecule family and is expressed on both resting CD4+CD25+ regulatory T (T(R)) cells and activated CD4+ T cells. We investigated the endogenous mechanisms that regulate GITR expression on both T(R) and CD4+ T cells, as well as the functional interaction between GITR and other costimulatory molecules. CD28 stimulation increased GITR expression on both T(R) and CD4+ T cells via IL-2-dependent mechanisms. In addition, ligation of GITR and/or CD28 increased the level of CD4+ T cell proliferation and effector function under both APC-dependent and -independent conditions, suggesting that these costimulatory molecules cooperate to regulate CD4+ T cell activation and function by directly signaling to the CD4+ T cell. Thus, GITR may serve opposing functional roles on CD4+ T(R) and effector cells and alterations in GITR expression and/or function may tip the balance between immune tolerance and effector function.
authors.affiliation: Department of Microbiology-Immunology and the Interdepartmental Immunobiology Center, Feinberg School of Medicine, Northwestern University, Chicago, IL 60611, USA.
authors.forename: Adam P
authors.initials: AP
authors.lastname: Kohm
authors.forename: Joseph R
authors.initials: JR
authors.lastname: Podojil
authors.forename: Julie S
authors.initials: JS
authors.lastname: Williams
authors.forename: Jeffrey S
authors.initials: JS
authors.lastname: McMahon
authors.forename: Stephen D
authors.initials: SD
authors.lastname: Miller
mesh_terms: D000818:Animals; D000911:Antibodies, Monoclonal; D018106:CD28 Antigens / Q000502:physiology*; D002478:Cells, Cultured; D005786:Gene Expression Regulation / Q000276:immunology*; D053450:Glucocorticoid-Induced TNFR-Related Protein; D005938:Glucocorticoids / Q000502:physiology*; D007376:Interleukin-2 / Q000235:genetics / Q000502:physiology*; D051379:Mice; D008807:Mice, Inbred BALB C; D008822:Mice, Transgenic; D005810:Multigene Family / Q000276:immunology*; D012333:RNA, Messenger / Q000378:metabolism; D015375:Receptors, Interleukin-2 / Q000172:deficiency / Q000235:genetics / Q000378:metabolism; D017475:Receptors, Nerve Growth Factor / Q000096:biosynthesis* / Q000235:genetics*; D018124:Receptors, Tumor Necrosis Factor / Q000096:biosynthesis* / Q000235:genetics*; D011994:Recombinant Proteins / Q000235:genetics / Q000378:metabolism; D050378:T-Lymphocytes, Regulatory / Q000276:immunology / Q000502:physiology*
chemical_list: D000911:Antibodies, Monoclonal; D018106:CD28 Antigens; D053450:Glucocorticoid-Induced TNFR-Related Protein; D005938:Glucocorticoids; D007376:Interleukin-2; D012333:RNA, Messenger; D015375:Receptors, Interleukin-2; D017475:Receptors, Nerve Growth Factor; D018124:Receptors, Tumor Necrosis Factor; D011994:Recombinant Proteins; C106544:Tnfrsf18 protein, mouse