The intestinal immune system has the challenging task of tolerating foreign nutrients and the commensal microbiome, while excluding or eliminating ingested pathogens. Failure of this balance leads to conditions such as inflammatory bowel diseases, food allergies and invasive gastrointestinal infections1. Multiple immune mechanisms are therefore in place to maintain tissue integrity, including balanced generation of effector T (TH) cells and FOXP3+ regulatory T (pTreg) cells, which mediate resistance to pathogens and regulate excessive immune activation, respectively1,2,3,4. The gut-draining lymph nodes (gLNs) are key sites for orchestrating adaptive immunity to luminal perturbations5,6,7. However, it is unclear how they simultaneously support tolerogenic and inflammatory reactions. Here we show that gLNs are immunologically specific to the functional gut segment that they drain. Stromal and dendritic cell gene signatures and polarization of T cells against the same luminal antigen differ between gLNs, with the proximal small intestine-draining gLNs preferentially giving rise to tolerogenic responses and the distal gLNs to pro-inflammatory T cell responses. This segregation permitted the targeting of distal gLNs for vaccination and the 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, with effects on 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 antigen targeting to specific gut segments for therapeutic immune modulation.
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Source data for all figures are provided with the paper. For RNA-seq experiments the raw and processed data generated here can be obtained at the Gene Expression Omnibus database under the accession code: GSE121811.
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We thank all members of the Mucida laboratory, past and present, for assistance, discussions and reading of the manuscript; B. Reis for figure preparation; F. Matheis for propagating S. venezuelensis; A. Rogoz and S. Gonzalez for the maintenance of mice; T. Rendon and B. Lopez for genotyping; K. Gordon and K. Chosphel for assistance with cell sorting; the Rockefeller University Bio-imaging Research Center for assistance with microscopy and image analysis; the Rockefeller University Genomics Center for RNA sequencing; Rockefeller University employees for assistance; M. Nussenzweig, G. Victora and J. Lafaille and their respective laboratory members for discussions and suggestions; D. Littman and M. Xu (NYU) for 7B8tg mice and faeces from SFB monocolonized mice; and S. Galli and K. Matsushita (Stanford University) for providing S. venezuelensis and guidance on how to maintain it. This work was supported by a Swiss National Science Foundation postdoctoral fellowship and University of Chicago start-up funds (D.E.); a CAPES fellowship (M.C.C.C.); an NIH F31 Kirchstein Fellowship, Philip M. Levine Fellowship, and Kavli Neural Systems Institute Graduate Fellowship (P.A.M.); the Leona M. and Harry B. Helmsley Charitable Trust, the Crohn’s & Colitis Foundation of America Senior Research Award, the Burroughs Wellcome Fund PATH Award, and National Institute of Health grants R21AI31188, R01DK113375 and R01DK093674 (D.M.).
Nature thanks Rodney Newberry and the other anonymous reviewer(s) for their contribution to the peer review of this work.