iNKT cells, the microbiota & intestinal inflammation

Inflammatory bowel disease (IBD) is a spectrum of chronic inflammatory disorders of the gastrointestinal tract that has genetic and environmental components. IBD is typically described as deregulated immune responses towards the intestinal microbiota, whereby T cells play a prominent role. Invariant Natural Killer T (iNKT) cells are a subset of innate lipid-reactive T cells that are very conserved across mammals. iNKT cells are functionally versatile, and can influence immune outcomes in a wide range of diseases, including IBD. These cells appear to be protective and deleterious in T_H1 and T_H2 models of colitis, respectively. Comparison of iNKT cell-deficient and sufficient mice during DSS colitis has yielded inconsistent results. Here we show that CD1d KO mice that lack iNKT cells have profound intestinal microbiota alterations compared to their wild-type counterpart, which is associated with increased sensitivity to DSS. However, microbiota differences and DSS sensitivity are abrogated in CD1d-deficient and sufficient littermate mice. Fecal transplant of CD1d KO microbiota into wild-type recipient mice induces basal intestinal inflammation, which is exacerbated upon DSS treatment. This shows that CD1d KO mice harbor a pro-inflammatory microbiota. Finally, treatment with the prototypical iNKT cell ligand a-galactosylceramide suggests that the microbiota influences iNKT cell response and function during intestinal inflammation. We currently investigate how iNKT cells and the microbiota influence each other, and the impact of this bidirectional relationship on the establishment of intestinal inflammation. Identification of these mechanisms may lead to new therapeutic strategies targeting iNKT cells for the treatment of IBD.