Gut microbiota regulates NKG2D ligand expression on intestinal epithelial cells

Eur J Immunol. 2013 Feb;43(2):447-57. doi: 10.1002/eji.201242462. Epub 2012 Dec 12.


Intestinal epithelial cells (IECs) are one of a few cell types in the body with constitutive surface expression of natural killer group 2 member D (NKG2D) ligands, although the magnitude of ligand expression by IECs varies. Here, we investigated whether the gut microbiota regulates the NKG2D ligand expression on small IECs. Germ-free and ampicillin-treated mice were shown to have a significant increase in NKG2D ligand expression. Interestingly, vancomycin treatment, which propagated the bacterium Akkermansia muciniphila and reduced the level of IFN-γ and IL-15 in the intestine, decreased the NKG2D ligand expression on IECs. In addition, a similar increase in A. muciniphila and a decreased NKG2D ligand expression was seen after feeding with dietary xylooligosaccharides. A pronounced increase in NKG2D ligand expression was furthermore observed in IL-10-deficient mice. In summary, our results suggest that the constitutive levels of NKG2D ligand expression on IECs are regulated by microbial signaling in the gut and further disfavor the intuitive notion that IEC NKG2D ligand expression is caused by low-grade immune reaction against commensal bacteria. It is more likely that constitutively high IEC NKG2D ligand expression is kept in check by an intestinal regulatory immune milieu induced by members of the gut microbiota, for example A. muciniphila.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Ampicillin / pharmacology
  • Animals
  • Epithelial Cells / immunology*
  • Epithelial Cells / metabolism
  • Epithelial Cells / microbiology*
  • Feces / microbiology
  • Female
  • Glucuronates / immunology
  • Interferon-gamma / immunology
  • Interferon-gamma / metabolism
  • Interleukin-10 / immunology
  • Interleukin-10 / metabolism
  • Interleukin-15 / immunology
  • Interleukin-15 / metabolism
  • Intestine, Small / cytology
  • Intestine, Small / immunology
  • Intestine, Small / metabolism*
  • Intestine, Small / microbiology*
  • Ligands
  • Male
  • Metagenome / immunology*
  • Mice
  • Mice, Inbred C57BL
  • Minor Histocompatibility Antigens / immunology
  • Minor Histocompatibility Antigens / metabolism
  • NK Cell Lectin-Like Receptor Subfamily K / biosynthesis*
  • NK Cell Lectin-Like Receptor Subfamily K / immunology
  • NK Cell Lectin-Like Receptor Subfamily K / metabolism
  • Nuclear Matrix-Associated Proteins / immunology
  • Nuclear Matrix-Associated Proteins / metabolism
  • Nucleocytoplasmic Transport Proteins / immunology
  • Nucleocytoplasmic Transport Proteins / metabolism
  • Oligosaccharides / immunology
  • Signal Transduction / immunology
  • Vancomycin / pharmacology


  • Glucuronates
  • Interleukin-15
  • Klrk1 protein, mouse
  • Ligands
  • Minor Histocompatibility Antigens
  • NK Cell Lectin-Like Receptor Subfamily K
  • Nuclear Matrix-Associated Proteins
  • Nucleocytoplasmic Transport Proteins
  • Oligosaccharides
  • Rae1 protein, mouse
  • minor H antigen H60
  • xylooligosaccharide
  • Interleukin-10
  • Vancomycin
  • Ampicillin
  • Interferon-gamma