title: Co-inhibitory roles for glucocorticoid-induced TNF receptor in CD1d-dependent natural killer T cells.
abstract: Invariant natural killer T (iNKT) cells are a special subset of alphabeta T cells with invariant TCR, which recognize alpha-galactosylceramide (alpha-GalCer) presented by CD1d. In addition to signals through the invariant TCR upon stimulation with alpha-GalCer, costimulatory signals, such as signals through CD28 and OX40, are indispensable for full activation of iNKT cells. In this study, we investigated the functions of a well-known costimulatory molecule, glucocorticoid-induced TNF receptor (GITR), on Ag-induced iNKT cell activation. Unexpectedly, engagement of GITR by agonistic mAb DTA-1 suppressed proliferation and cytokine production of iNKT cells upon alpha-GalCer stimulation. In addition, GITR signals in iNKT cells during only the Ag-priming phase was sufficient to inhibit the iNKT cell activation. Consistent with these results, the GITR-deficient iNKT cells showed enhanced proliferation and increased cytokine production upon alpha-GalCer stimulation both in vitro and in vivo. Furthermore, the in vivo administration of alpha-GalCer suppressed tumor metastasis more efficiently in GITR-deficient mice than in wild-type mice. Collectively, GITR plays a co-inhibitory role in Ag-induced iNKT cell activation.
authors.affiliation: Department of Microbiology and Immunology, Tohoku University Graduate School of Medicine, Sendai, Japan.
authors.forename: Shuming
authors.initials: S
authors.lastname: Chen
authors.forename: Lishomwa C
authors.initials: LC
authors.lastname: Ndhlovu
authors.forename: Takeshi
authors.initials: T
authors.lastname: Takahashi
authors.forename: Kazuyoshi
authors.initials: K
authors.lastname: Takeda
authors.forename: Yoshinori
authors.initials: Y
authors.lastname: Ikarashi
authors.forename: Toshiaki
authors.initials: T
authors.lastname: Kikuchi
authors.forename: Kazuko
authors.initials: K
authors.lastname: Murata
authors.forename: Pier Paolo
authors.initials: PP
authors.lastname: Pandolfi
authors.forename: Carlo
authors.initials: C
authors.lastname: Riccardi
authors.forename: Masao
authors.initials: M
authors.lastname: Ono
authors.forename: Kazuo
authors.initials: K
authors.lastname: Sugamura
authors.forename: Naoto
authors.initials: N
authors.lastname: Ishii
mesh_terms: D000818:Animals; D018949:Antigens, CD1 / Q000502:physiology*; D055610:Antigens, CD1d; D003602:Cytotoxicity, Immunologic; D005699:Galactosylceramides / Q000494:pharmacology; D005938:Glucocorticoids / Q000494:pharmacology*; D007694:Killer Cells, Natural / Q000276:immunology*; D008213:Lymphocyte Activation; D051379:Mice; D008810:Mice, Inbred C57BL; D018124:Receptors, Tumor Necrosis Factor / Q000502:physiology*
chemical_list: D018949:Antigens, CD1; D055610:Antigens, CD1d; D005699:Galactosylceramides; D005938:Glucocorticoids; D018124:Receptors, Tumor Necrosis Factor; C493154:alpha-galactosylceramide