NOD2 regulates intestinal intraepithelial lymphocyte homeostasis

▸ Jiang W, Wang X, Zeng B, et al. Recognition of gut microbiota by NOD2 is essential for the homeostasis of intestinal intraepithelial lymphocytes. J Exp Med 2013;210:2465-76.

NOD2 is an intracellular sensor for microbial pathogens and plays a vital role in epithelial defense. It was the first identified gene to be strongly associated with susceptibility to Crohn's disease (CD). While studies suggest that loss-of-function mutation leads to reduced antimicrobial resistance and impaired innate immunity in CD, it is not clear how this mutation contributes to the pathogenesis of CD. Intestinal intraepithelial lymphocytes (IELs) play an important role in the homeostasis of the intestinal mucosa and have a protective function in inflammatory bowel disease. Nod2^−/− mice have an impaired intestinal barrier function and increased susceptibility to colitis; however, whether NOD2 affects IEL homeostasis remains to be determined. In this study, the authors set out to investigate the role of Nod2 signalling in the maintenance of IELs using Nod2^−/− mice. Nod2 deficiency dramatically reduced the number of intestinal IELs in small and large intestines and the residual IELs exhibited poorer proliferation and higher apoptosis. Nod2 expression and IEL maintenance in the intestine are both dependent on the presence of gut microbiota. Depletion of the gut microbiota by antibiotics reduced the IEL numbers in the intestine and addition of a NOD2 agonist was able to recover the IELs, indicating that Nod2 signalling maintains the IELs via sensing gut microbiota. IL-15 expression, which is critical for IEL survival and homeostasis in the gut, was impaired in antigen-presenting cells of Nod2^−/− mice. Exogenous IL-15 rescued the IEL loss caused by Nod2 deletion. Importantly, recovery of IELs by adoptive transfer to Nod2^−/− mice reduced the susceptibility of these mice to colitis. This study demonstrates that Nod2 signalling has an important role in …