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Microbiota restricts trafficking of bacteria to mesenteric lymph nodes by CX3CR1hi cells

Nature volume 494, pages 116–120 (2013)Cite this article

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Abstract

The intestinal microbiota has a critical role in immune system and metabolic homeostasis, but it must be tolerated by the host to avoid inflammatory responses that can damage the epithelial barrier separating the host from the luminal contents1,2,3,4,5,6. Breakdown of this regulation and the resulting inappropriate immune response to commensals are thought to lead to the development of inflammatory bowel diseases such as Crohn’s disease and ulcerative colitis7. We proposed that the intestinal immune system is instructed by the microbiota to limit responses to luminal antigens. Here we demonstrate in mice that, at steady state, the microbiota inhibits the transport of both commensal and pathogenic bacteria from the lumen to a key immune inductive site, the mesenteric lymph nodes (MLNs). However, in the absence of Myd88 or under conditions of antibiotic-induced dysbiosis, non-invasive bacteria were trafficked to the MLNs in a CCR7-dependent manner, and induced both T-cell responses and IgA production. Trafficking was carried out by CX3CR1hi mononuclear phagocytes, an intestinal-cell population previously reported to be non-migratory8. These findings define a central role for commensals in regulating the migration to the MLNs of CX3CR1hi mononuclear phagocytes endowed with the ability to capture luminal bacteria, thereby compartmentalizing the intestinal immune response to avoid inflammation.

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Figure 1: Induction of immune response against non-invasive Salmonella after antibiotic treatment.
Figure 2: MyD88-dependent signals limit non-invasive Salmonella entry in the MLN.
Figure 3: Colonization of MLNs by non-invasive Salmonella requires CCR7-dependent trafficking of CX 3CR1 hi cells.
Figure 4: CD103 − CX 3CR1 + cells migrate into afferent lymphatics of antibiotic-treated animals.

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Acknowledgements

We thank H. Yue and J. Hall for comments on the manuscript and members of the Littman laboratory for their suggestions. We thank the NYU Histology Core, which is supported in part by grant 5P30CA016087-32 from the National Cancer Institute. Supported by the American Cancer Society and National Institutes of Health (NIH) T32 CA009161 (G.E.D.), NIH T32 DK083256-02 (R.S.L.), Human Frontier Science Program Long-Term Fellowship (B.B.), NIH R01AI085166 (S.R.S.) and the Howard Hughes Medical Institute (D.R.L.).

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Author notes

  1. Jing-Xin Zhang & Beatrice Breart

    Present address: Present addresses: Sanofi Oncology, Cambridge, Massachusetts 02139, USA (J.-X.Z.); Dynamics of Immune Responses, Institut Pasteur, 75015 Paris, France, and Institut National de la Santé et de la Recherche Médicale U668, Equipe Avenir, 75015 Paris, France (B.B.).,

  2. Randy S. Longman and Jing-Xin Zhang: These authors contributed equally to this work.

Authors and Affiliations

  1. Molecular Pathogenesis Program, The Kimmel Center for Biology and Medicine of the Skirball Institute, New York University School of Medicine, New York, New York 10016, USA ,

    Gretchen E. Diehl, Randy S. Longman, Jing-Xin Zhang, Beatrice Breart, Carolina Galan, Adolfo Cuesta, Susan R. Schwab & Dan R. Littman

  2. Division of Digestive and Liver Diseases, Department of Medicine, Columbia University, New York, New York 10032, USA,

    Randy S. Longman

  3. Howard Hughes Medical Institute, New York University School of Medicine, New York, New York 10016, USA ,

    Adolfo Cuesta & Dan R. Littman

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  1. Gretchen E. Diehl
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Contributions

G.E.D. designed and performed the experiments. G.E.D. and D.R.L planned experiments and wrote the manuscript with input from all co-authors. R.S.L., J.-X.Z., S.R.S., B.B., C.G. and A.C. helped plan and perform experiments.

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Correspondence to Gretchen E. Diehl.

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Diehl, G., Longman, R., Zhang, JX. et al. Microbiota restricts trafficking of bacteria to mesenteric lymph nodes by CX3CR1hi cells. Nature 494, 116–120 (2013). https://doi.org/10.1038/nature11809

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