title: Costimulation via glucocorticoid-induced TNF receptor in both conventional and CD25+ regulatory CD4+ T cells.
abstract: The glucocorticoid-induced TNF receptor (GITR), which is a member of the TNF receptor family, is expressed preferentially at high levels on CD25+CD4+ regulatory T cells and plays a key role in the peripheral tolerance that is mediated by these cells. GITR is also expressed on conventional CD4+ and CD8+ T cells, and its expression is enhanced rapidly after activation. In this report we show that the GITR provides a potent costimulatory signal to both CD25+ and CD25- CD4+ T cells. GITR-mediated stimulation induced by anti-GITR mAb DTA-1 or GITR ligand transfectants efficiently augmented the proliferation of both CD25-CD4+ and CD25+CD4+ T cells under the limited dose of anti-CD3 stimulation. The augmentation of T cell activation was further confirmed by the enhanced cell cycle progression; early induction of the activation Ags, CD69 and CD25; cytokine production, such as IL-2, IFN-gamma, IL-4, and IL-10; anti-CD3-induced redirected cytotoxicity; and intracellular signaling, assessed by translocation of NF-kappaB components. GITR costimulation showed a potent ability to produce high amounts of IL-10, which resulted in counter-regulation of the enhanced proliferative responses. Our results highlight evidence that GITR acts as a potent and unique costimulator for an early CD4+ T cell activation.
authors.affiliation: Department of Molecular Immunology, Graduate School, Tokyo Medical and Dental University, 1-5-45 Yushima, Bunkyo-ku, Tokyo 113-8549, Japan.
authors.forename: Fumiko
authors.initials: F
authors.lastname: Kanamaru
authors.forename: Pornpan
authors.initials: P
authors.lastname: Youngnak
authors.forename: Masaaki
authors.initials: M
authors.lastname: Hashiguchi
authors.forename: Tomohisa
authors.initials: T
authors.lastname: Nishioka
authors.forename: Takeshi
authors.initials: T
authors.lastname: Takahashi
authors.forename: Shimon
authors.initials: S
authors.lastname: Sakaguchi
authors.forename: Isao
authors.initials: I
authors.lastname: Ishikawa
authors.forename: Miyuki
authors.initials: M
authors.lastname: Azuma
mesh_terms: D000818:Animals; D015703:Antigens, CD / Q000096:biosynthesis; D000945:Antigens, Differentiation, T-Lymphocyte / Q000096:biosynthesis; D017252:CD3 Complex / Q000378:metabolism; D015496:CD4-Positive T-Lymphocytes / Q000378:metabolism*; D002455:Cell Division; D045744:Cell Line, Tumor; D016207:Cytokines / Q000096:biosynthesis; D005260:Female; D053450:Glucocorticoid-Induced TNFR-Related Protein; D037181:Lectins, C-Type; D008213:Lymphocyte Activation; D051379:Mice; D008807:Mice, Inbred BALB C; D016328:NF-kappa B / Q000378:metabolism; D015375:Receptors, Interleukin-2 / Q000096:biosynthesis; D017475:Receptors, Nerve Growth Factor / Q000032:analysis / Q000378:metabolism / Q000502:physiology*; D018124:Receptors, Tumor Necrosis Factor / Q000032:analysis / Q000378:metabolism / Q000502:physiology*; D015398:Signal Transduction; D013154:Spleen / Q000166:cytology; D000099192:CD69 Antigens
chemical_list: D015703:Antigens, CD; D000945:Antigens, Differentiation, T-Lymphocyte; D017252:CD3 Complex; D016207:Cytokines; D053450:Glucocorticoid-Induced TNFR-Related Protein; D037181:Lectins, C-Type; D016328:NF-kappa B; D015375:Receptors, Interleukin-2; D017475:Receptors, Nerve Growth Factor; D018124:Receptors, Tumor Necrosis Factor; D000099192:CD69 Antigens; C106544:Tnfrsf18 protein, mouse