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

Crohn’s disease (CD) involves aberrant intestinal T cell immunity, and genetic variants associated with disease development. Notably, mutations impairing NOD2 signaling represent the largest genetic risk factor for CD. Paradoxically, while variants in NOD2 are associated CD, its ligand, bacterial muramyl dipeptide (MDP) is a potent stimulator of innate immunity, long recognized as the minimal component required for the adjuvanticity of Complete Freund’s Adjuvant. This paradox underscores a critical gap in our understanding of how NOD2 coordinates the innate-adaptive immune crosstalk required to maintain intestinal homeostasis. Here, we show that NOD2 engagement by MDP drives T cell homing to the mesenteric lymph nodes during homeostasis and infection. This recruitment promotes antigen-specific effector and memory T cell accumulation in the ileal lamina propria, a process essential for effective recall responses and clearance of secondary infections. Mechanistically, this process requires endothelial-intrinsic NOD2 expression, which drives a specialized transcriptional program for leukocyte recruitment.