Microbial flora drives interleukin 22 production in intestinal NKp46+ cells that provide innate mucosal immune defense

Immunity. 2008 Dec 19;29(6):958-70. doi: 10.1016/j.immuni.2008.11.001. Epub 2008 Dec 11.


Natural killer (NK) cells are innate lymphocytes with spontaneous antitumor activity, and they produce interferon-gamma (IFN-gamma) that primes immune responses. Whereas T helper cell subsets differentiate from naive T cells via specific transcription factors, evidence for NK cell diversification is limited. In this report, we characterized intestinal lymphocytes expressing the NK cell natural cytotoxicity receptor NKp46. Gut NKp46+ cells were distinguished from classical NK cells by limited IFN-gamma production and absence of perforin, whereas several subsets expressed the nuclear hormone receptor retinoic acid receptor-related orphan receptor t (RORgammat) and interleukin-22 (IL-22). Intestinal NKp46+IL-22+ cells were generated via a local process that was conditioned by commensal bacteria and required RORgammat. Mice lacking IL-22-producing NKp46+ cells showed heightened susceptibility to the pathogen Citrobacter rodentium, consistent with a role for intestinal NKp46+ cells in immune protection. RORgammat-driven diversification of intestinal NKp46+ cells thereby specifies an innate cellular defense mechanism that operates at mucosal surfaces.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Antigens, Ly / immunology*
  • Antigens, Ly / metabolism
  • Citrobacter rodentium / immunology*
  • Enterobacteriaceae Infections / immunology*
  • Enterobacteriaceae Infections / microbiology
  • Immunity, Innate
  • Immunity, Mucosal / immunology
  • Interleukin-22
  • Interleukins / immunology*
  • Interleukins / metabolism
  • Intestinal Mucosa / metabolism
  • Intestines / immunology*
  • Intestines / microbiology
  • Killer Cells, Natural / immunology*
  • Killer Cells, Natural / metabolism
  • Mice
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Natural Cytotoxicity Triggering Receptor 1 / immunology*
  • Natural Cytotoxicity Triggering Receptor 1 / metabolism
  • Nuclear Receptor Subfamily 1, Group F, Member 3
  • Perforin / immunology
  • Perforin / metabolism
  • Receptors, Retinoic Acid / immunology
  • Receptors, Retinoic Acid / metabolism
  • Receptors, Thyroid Hormone / immunology
  • Receptors, Thyroid Hormone / metabolism
  • Signal Transduction / immunology


  • Antigens, Ly
  • Interleukins
  • Natural Cytotoxicity Triggering Receptor 1
  • Ncr1 protein, mouse
  • Nuclear Receptor Subfamily 1, Group F, Member 3
  • Receptors, Retinoic Acid
  • Receptors, Thyroid Hormone
  • Rorc protein, mouse
  • Perforin