Journal
EUROPEAN JOURNAL OF IMMUNOLOGY
Volume 38, Issue 8, Pages 2229-2240Publisher
WILEY-V C H VERLAG GMBH
DOI: 10.1002/eji.200838167
Keywords
co-inhibitory signal; glucocorticoid-induced TNF receptor; invariant NKT cell
Categories
Funding
- Ministry of Education, Culture, Sports, Science and Technology of Japan
- Japan Society for the Promotion of Science
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Invariant natural killer T (iNKT) cells are a special subset of tip T cells with invariant TCR, which recognize a-galactosylceramide (a-GalCer) presented by CD1d. In addition to signals through the invariant TCR upon stimulation with (x-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 (x-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.
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