title: Regulation of murine inflammatory bowel disease by CD25+ and CD25- CD4+ glucocorticoid-induced TNF receptor family-related gene+ regulatory T cells.
abstract: CD4(+)CD25(+) regulatory T cells in normal animals are engaged in the maintenance of immunological self-tolerance and prevention of autoimmune disease. However, accumulating evidence suggests that a fraction of the peripheral CD4(+)CD25(-) T cell population also possesses regulatory activity in vivo. Recently, it has been shown glucocorticoid-induced TNFR family-related gene (GITR) is predominantly expressed on CD4(+)CD25(+) regulatory T cells. In this study, we show evidence that CD4(+)GITR(+) T cells, regardless of the CD25 expression, regulate the mucosal immune responses and intestinal inflammation. SCID mice restored with the CD4(+)GITR(-) T cell population developed wasting disease and severe chronic colitis. Cotransfer of CD4(+)GITR(+) population prevented the development of CD4(+)CD45RB(high) T cell-transferred colitis. Administration of anti-GITR mAb-induced chronic colitis in mice restored both CD45RB(high) and CD45RB(low) CD4(+) T cells. Interestingly, both CD4(+)CD25(+) and CD4(+)CD25(-) GITR(+) T cells prevented wasting disease and colitis. Furthermore, in vitro studies revealed that CD4(+)CD25(-)GITR(+) T cells as well as CD4(+)CD25(+)GITR(+) T cells expressed CTLA-4 intracellularly, showed anergic, suppressed T cell proliferation, and produced IL-10 and TGF-beta. These data suggest that GITR can be used as a specific marker for regulatory T cells controlling mucosal inflammation and also as a target for treatment of inflammatory bowel disease.
authors.affiliation: Department of Experimental Pathology, Institute for Frontier Medical Sciences, Kyoto University, Kyoto, Japan.
authors.forename: Koji
authors.initials: K
authors.lastname: Uraushihara
authors.forename: Takanori
authors.initials: T
authors.lastname: Kanai
authors.forename: Kwibeom
authors.initials: K
authors.lastname: Ko
authors.forename: Teruji
authors.initials: T
authors.lastname: Totsuka
authors.forename: Shin
authors.initials: S
authors.lastname: Makita
authors.forename: Ryoichi
authors.initials: R
authors.lastname: Iiyama
authors.forename: Tetsuya
authors.initials: T
authors.lastname: Nakamura
authors.forename: Mamoru
authors.initials: M
authors.lastname: Watanabe
mesh_terms: D000818:Animals; D000911:Antibodies, Monoclonal / Q000008:administration & dosage; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology / Q000378:metabolism / Q000637:transplantation; D002908:Chronic Disease; D003092:Colitis / Q000276:immunology / Q000517:prevention & control; D005260:Female; D005786:Gene Expression Regulation / Q000276:immunology; D053450:Glucocorticoid-Induced TNFR-Related Protein; D005938:Glucocorticoids / Q000502:physiology; D018928:Immunity, Mucosal / Q000235:genetics; D015212:Inflammatory Bowel Diseases / Q000276:immunology* / Q000473:pathology / Q000517:prevention & control*; D007274:Injections, Intraperitoneal; D017493:Leukocyte Common Antigens / Q000096:biosynthesis; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D016513:Mice, SCID; D005810:Multigene Family / Q000276:immunology*; D015375:Receptors, Interleukin-2 / Q000096:biosynthesis*; D017475:Receptors, Nerve Growth Factor / Q000096:biosynthesis* / Q000276:immunology; D018124:Receptors, Tumor Necrosis Factor / Q000096:biosynthesis* / Q000235:genetics* / Q000276:immunology; D013154:Spleen / Q000166:cytology / Q000276:immunology / Q000378:metabolism / Q000637:transplantation; D016176:T-Lymphocyte Subsets / Q000276:immunology* / Q000378:metabolism / Q000637:transplantation
chemical_list: D000911:Antibodies, Monoclonal; D053450:Glucocorticoid-Induced TNFR-Related Protein; D005938:Glucocorticoids; D015375:Receptors, Interleukin-2; D017475:Receptors, Nerve Growth Factor; D018124:Receptors, Tumor Necrosis Factor; C106544:Tnfrsf18 protein, mouse; D017493:Leukocyte Common Antigens