Antigen-specific cytotoxicity by invariant NKT cells in vivo is CD95/CD178-dependent and is correlated with antigenic potency

J Immunol. 2010 Sep 1;185(5):2721-9. doi: 10.4049/jimmunol.1001018. Epub 2010 Jul 26.


Invariant NKT (iNKT) cells are a unique subset of T lymphocytes that rapidly carry out effector functions following activation with glycolipid Ags, such as the model Ag alpha-galactosylceramide. Numerous studies have investigated the mechanisms leading to Th1 and Th2 cytokine production by iNKT cells, as well as the effects of the copious amounts of cytokines these cells produce. Less is known, however, about the mechanisms of iNKT cell cytotoxicity. In this study, we investigated the effect of Ag availability and strength, as well as the molecules involved in iNKT cytotoxicity. We demonstrate that the iNKT cell cytotoxicity in vivo correlates directly with the amount of CD1d expressed by the targets as well as the TCR affinity for the target glycolipid Ag. iNKT cells from spleen, liver, and thymus were comparable in their cytotoxicity in vitro. Surprisingly, we show that the Ag-specific cytotoxicity of iNKT cells in vivo depended almost exclusively on the interaction of CD95 (Fas) with CD178 (FasL), and that this mechanism can be efficiently used for tumor protection. Therefore, unlike NK cells, which rely mostly on perforin/granzyme-mediated mechanisms, the Ag-specific cytotoxicity of iNKT cells in vivo is largely restricted to the CD95/CD178 pathway.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Antigens, CD1d / biosynthesis
  • Antigens, CD1d / physiology
  • Cell Line, Tumor
  • Cytotoxicity Tests, Immunologic* / methods
  • Epitopes, T-Lymphocyte / immunology*
  • Epitopes, T-Lymphocyte / toxicity
  • Fas Ligand Protein / metabolism
  • Fas Ligand Protein / physiology*
  • Galactosylceramides / toxicity
  • Lung Neoplasms / immunology
  • Lung Neoplasms / pathology
  • Lung Neoplasms / therapy
  • Melanoma, Experimental / immunology
  • Melanoma, Experimental / pathology
  • Melanoma, Experimental / therapy
  • Mice
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Mice, Transgenic
  • Natural Killer T-Cells / immunology*
  • Natural Killer T-Cells / metabolism
  • Natural Killer T-Cells / pathology
  • Up-Regulation / immunology
  • fas Receptor / metabolism
  • fas Receptor / physiology*


  • Antigens, CD1d
  • Cd1d1 protein, mouse
  • Epitopes, T-Lymphocyte
  • Fas Ligand Protein
  • Galactosylceramides
  • alpha-galactosylceramide
  • fas Receptor