Co-inhibitory roles for glucocorticoid-induced TNF receptor in CD1d-dependent natural killer T cells.
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.
Chen
Shuming
S
Department of Microbiology and Immunology, Tohoku University Graduate School of Medicine, Sendai, Japan.
Ndhlovu
Lishomwa C
LC
Takahashi
Takeshi
T
Takeda
Kazuyoshi
K
Ikarashi
Yoshinori
Y
Kikuchi
Toshiaki
T
Murata
Kazuko
K
Pandolfi
Pier Paolo
PP
Riccardi
Carlo
C
Ono
Masao
M
Sugamura
Kazuo
K
Ishii
Naoto
N
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*
D018949:Antigens, CD1; D055610:Antigens, CD1d; D005699:Galactosylceramides; D005938:Glucocorticoids; D018124:Receptors, Tumor Necrosis Factor; C493154:alpha-galactosylceramide