Co-inhibitory roles for glucocorticoid-induced TNF receptor in CD1d-dependent natural killer T cells

Eur J Immunol. 2008 Aug;38(8):2229-40. doi: 10.1002/eji.200838167.


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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Antigens, CD1 / physiology*
  • Antigens, CD1d
  • Cytotoxicity, Immunologic
  • Galactosylceramides / pharmacology
  • Glucocorticoids / pharmacology*
  • Killer Cells, Natural / immunology*
  • Lymphocyte Activation
  • Mice
  • Mice, Inbred C57BL
  • Receptors, Tumor Necrosis Factor / physiology*


  • Antigens, CD1
  • Antigens, CD1d
  • Galactosylceramides
  • Glucocorticoids
  • Receptors, Tumor Necrosis Factor
  • alpha-galactosylceramide