Endothelial cell-intrinsic NOD2 signaling regulates the intestinal immune response through the generation of effector and memory T cells.

Abstract

Crohns disease (CD) is marked by vascular endothelial dysfunction and aberrant T cell immunity in the gastrointestinal tract. However, mechanistic understanding is lacking of how CD-associated gene variants, particularly those that compromise NOD2 function, impact the intestinal vascular endothelium and orchestration of T cell immunity. Here, we find that NOD2, when triggered by its ligand, muramyl dipeptide, is unique among pattern recognition receptors in its ability to induce endothelial cell expression of chemokines and immune adhesion molecules. Consequently, NOD2 signaling promoted T cell homing specifically to gut-associated lymphoid tissue during intestinal infection. Endothelial cell-specific deletion of Nod2 resulted in fewer effector and memory T cells in the small intestine, impacting the hosts ability to clear secondary infection. Together, our findings suggest that vascular endothelial cell expression of NOD2 coordinates intestinal immune responses, and that CD-associated loss of NOD2 function promotes aberrant inflammation due to alterations in the magnitude and specificity of host defense within the intestine.