Gut microbiota regulates NKG2D ligand expression on intestinal epithelial cells

Abstract

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. Keywords:Gut microbiota r IL-10 r Intestinal epithelial cells r NKG2D ligands IntroductionCommensal bacteria are important in maintaining immune tolerance and intestinal epithelial barrier integrity. As such, the commensal microbiota is an integral part of the normal gut. It is tolerated by the mucosal immune system [1], which however may rapidly switch from its suppressive state to become activated upon pathogen engagement [2]. The natural killer group 2 member D (NKG2D)/NKG2D ligand interaction is part of this immunological sensor system that detects malfunctioning. Chronic inflammatory Correspondence: Dr. Camilla H. F. Hansen e-mail: camfriis@sund.ku.dk conditions in the gut such as the autoimmune celiac disease and Crohn's disease in humans, and colitis in mice, are associated with increased surface expression of NKG2D ligands on intestinal epithelial cells (IECs) and lamina propria dendritic cells [3][4][5][6] which is also observed after infection with certain pathogenic strains of Escherichia coli [7].NKG2D ligands belong to the nonclassical MHC class I molecules and include MICA, MICB, and ULBP 1-6 proteins in human [8,9] and the H60a/-b/-c, Rae-1, and Mult1 proteins in mice [10]. Their expression levels are generally low, but are greatly enhanced during specific types of cellular stress, including inflammation and neoplastic transformation [11]. IECs were recognized early on as one of the few cell types in the body with constitutive surface expression of NKG2D ligands [12]; however, The regulation of NKG2D ligand surface expression has been intensely studied. However, a unifying controlling mechanism, if one exists, has not yet been established. It is clear that NK...

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