Microbiota Sensing by Nod2 Regulates Mucosal Damage in Small Intestinal Crypt Following Acute T cell Activation.

The high numbers of T cells in the inflamed intestinal mucosa and the requirement for T cells in various animal models of chronic intestinal inflammation suggest a key role of T cells in the pathogenesis of Inflammatory Bowel Diseases. Loss-of-function mutations in the NOD2 gene were the first defined genetic risk factors identified for Crohn's Disease. In this study, we used a murine model of T cell-induced enteropathy to examine the role of Nod2 in regulating immune activation and T cell-induced small intestine mucosal damage. We found that acute T cell activation induced more severe damage in crypt architecture, epithelial apoptosis and delayed mucosal healing in NOD2^-/- mice. Immune and inflammatory responses were also up-regulated as observed by the accumulation of Th17 cells and notably IFN-γ expressing Th17 cells. Small intestine mucosal damage required accumulation of microbiota dependent T cells as shown by the absence of mucosal damage in germ free mice. The delay in mucosal healing was prevented by antibiotic treatment indicating that microbiota sensing by Nod2 was important to control healing of mucosal damage in response to acute T cell activation. Our results demonstrate that Nod2 is an important regulator of mucosal damage following acute T cell activation.