Compartmentalized gut lymph node drainage dictates adaptive immune responses

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 severe diseases such as inflammatory bowel diseases (IBD), food allergies or invasive gastrointestinal infections(1). Multiple immune mechanisms are therefore in place to maintain tissue integrity, including balanced generation of effector T (T(H)) cells and FOXP3(+) regulatory T (pTreg) cells, which mediate resistance to pathogens and regulate excessive immune activation, respectively(1–4). The gut–draining lymph nodes (gLNs) are critical sites for orchestrating adaptive immunity to luminal perturbations(5–7). 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 T cell polarization against the same luminal antigen differed between gLNs, the proximal small intestine–draining gLNs preferentially giving rise to tolerogenic and the distal gLNs to pro-inflammatory T cell responses. This segregation permitted targeting distal gLNs for vaccination and maintenance of duodenal pTreg cell induction during colonic infection. Conversely, the compartmentalized dichotomy was perturbed by surgical removal of select distal gLNs and duodenal infection, impacting both lymphoid organ and tissue immune responses. Our findings reveal that the conflict between tolerogenic and inflammatory intestinal responses is in part resolved by discrete gLN drainage, and encourage gut segment-specific antigen targeting for therapeutic immune modulation.