title: Stimulation of CD25(+)CD4(+) regulatory T cells through GITR breaks immunological self-tolerance.
abstract: CD25(+)CD4(+) regulatory T cells in normal animals are engaged in the maintenance of immunological self-tolerance. We show here that glucocorticoid-induced tumor necrosis factor receptor family-related gene (GITR, also known as TNFRSF18)--a member of the tumor necrosis factor-nerve growth factor (TNF-NGF) receptor gene superfamily--is predominantly expressed on CD25(+)CD4(+) T cells and on CD25(+)CD4(+)CD8(-) thymocytes in normal naïve mice. We found that stimulation of GITR abrogated CD25(+)CD4(+) T cell-mediated suppression. In addition, removal of GITR-expressing T cells or administration of a monoclonal antibody to GITR produced organ-specific autoimmune disease in otherwise normal mice. Thus, GITR plays a key role in dominant immunological self-tolerance maintained by CD25(+)CD4(+) regulatory T cells and could be a suitable molecular target for preventing or treating autoimmune disease.
authors.affiliation: Department of Immunopathology, Tokyo Metropolitan Institute of Gerontology, Tokyo 173-0015, Japan.
authors.forename: Jun
authors.initials: J
authors.lastname: Shimizu
authors.forename: Sayuri
authors.initials: S
authors.lastname: Yamazaki
authors.forename: Takeshi
authors.initials: T
authors.lastname: Takahashi
authors.forename: Yasumasa
authors.initials: Y
authors.lastname: Ishida
authors.forename: Shimon
authors.initials: S
authors.lastname: Sakaguchi
mesh_terms: D000818:Animals; D001327:Autoimmune Diseases / Q000209:etiology; D015704:CD4 Antigens / Q000302:isolation & purification; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology*; D019281:Dimerization; D053450:Glucocorticoid-Induced TNFR-Related Protein; D006023:Glycoproteins / Q000037:antagonists & inhibitors / Q000276:immunology / Q000378:metabolism; D007108:Immune Tolerance / Q000276:immunology*; D008198:Lymph Nodes / Q000276:immunology; D051379:Mice; D008807:Mice, Inbred BALB C; D051381:Rats; D017208:Rats, Wistar; D015375:Receptors, Interleukin-2 / Q000302:isolation & purification; D017475:Receptors, Nerve Growth Factor / Q000037:antagonists & inhibitors / Q000276:immunology / Q000378:metabolism*; D018124:Receptors, Tumor Necrosis Factor / Q000037:antagonists & inhibitors / Q000276:immunology / Q000378:metabolism*; D015398:Signal Transduction; D013154:Spleen / Q000276:immunology; D016176:T-Lymphocyte Subsets / Q000276:immunology*
chemical_list: D015704:CD4 Antigens; D053450:Glucocorticoid-Induced TNFR-Related Protein; D006023:Glycoproteins; D015375:Receptors, Interleukin-2; D017475:Receptors, Nerve Growth Factor; D018124:Receptors, Tumor Necrosis Factor; C106544:Tnfrsf18 protein, mouse