The pro-Th2 cytokine IL-33 directly interacts with invariant NKT and NK cells to induce IFN-gamma production

Eur J Immunol. 2009 Apr;39(4):1046-55. doi: 10.1002/eji.200838575.


IL-33 has recently been identified as a cytokine endowed with pro-Th2 functions, raising the question of its effect on invariant natural killer T cell (iNKT), which are potent IL-4 producers. Here, we report a two-fold increase of iNKT-cell counts in spleen and liver after a 7-day treatment of mice with IL-33, which results from a direct effect, given that purified iNKT cells express the T1/ST2 receptor constitutively and respond to IL-33 by in vitro expansion and functional activation. Conversely to the expected pro-Th2 effect, IL-33 induced a preferential increase in IFN-gamma rather than IL-4 production upon TCR engagement that depended on endogenous IL-12. Moreover, in combination with the pro-inflammatory cytokine IL-12, IL-33 enhanced IFN-gamma production by both iNKT and NK cells. Taken together these data support the conclusion that IL-33 can contribute as a co-stimulatory factor to innate cellular immune responses.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Female
  • Humans
  • Interferon-gamma / agonists
  • Interferon-gamma / immunology
  • Interferon-gamma / metabolism*
  • Interleukin-12 / immunology
  • Interleukin-12 / metabolism*
  • Interleukin-33
  • Interleukin-4 / agonists
  • Interleukin-4 / immunology
  • Interleukin-4 / metabolism
  • Interleukins / immunology*
  • Interleukins / pharmacology
  • Killer Cells, Natural / drug effects
  • Killer Cells, Natural / immunology*
  • Killer Cells, Natural / metabolism
  • Liver / drug effects
  • Liver / immunology
  • Liver / metabolism
  • Mice
  • Mice, Inbred BALB C
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Natural Killer T-Cells / drug effects
  • Natural Killer T-Cells / immunology*
  • Natural Killer T-Cells / metabolism
  • Spleen / drug effects
  • Spleen / immunology
  • Spleen / metabolism
  • Th2 Cells / drug effects
  • Th2 Cells / immunology*
  • Th2 Cells / metabolism


  • IL33 protein, human
  • Interleukin-33
  • Interleukins
  • Interleukin-12
  • Interleukin-4
  • Interferon-gamma