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

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.