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 αβ T cells with invariant TCR, which recognize α-galactosylceramide (α-GalCer) presented by CD1d. In addition to signals through the invariant TCR upon stimulation with α-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 α-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 α-GalCer stimulation both in vitro and in vivo. Furthermore, the in vivo administration of a-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.