Compartmentalized gut lymph node drainage dictates adaptive immune responses. mouse gut metagenome

The intestinal immune system has the challenging task of tolerating foreign nutrients and the commensal microbiome, while excluding or eliminating ingested pathogens. Failure in such balance leads to a range of severe systemic and intestinal diseases such as inflammatory bowel diseases, food allergies or invasive gastrointestinal infections1,2. Multiple innate and adaptive immune mechanisms are therefore in place to maintain tissue integrity, including efficient peripheral generation of effector T (TH) cells and FOXP3+ regulatory T (pTreg) cells, which mediate resistance to pathogens and regulate excessive immune activation, respectively2-5. The gut–draining lymph nodes (gLNs) are critical sites for orchestrating adaptive immunity to luminal perturbations6-8. However, how they manage to simultaneously support tolerogenic and inflammatory reactions is incompletely understood. Here we report that gLNs are immunologically unique according to the functional gut segment they drain. Stromal and dendritic cell gene signatures as well as adaptive T cell polarization against the same luminal antigen differed between gLNs along the intestine, the proximal small intestine–draining gLNs preferentially giving rise to tolerogenic and the distal gLNs to pro-inflammatory T cell responses. This compartmentalized dichotomy could be perturbed by duodenal infection, surgical removal of select distal gLNs, dysbiosis, or ectopic antigen delivery, impacting both lymphoid organ and tissue immune responses. Our findings reveal that the conflict between tolerogenic and inflammatory adaptive responses is in part resolved by discrete gLN drainage, and encourage gut segment-specific antigen targeting for therapeutic immune modulation.