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

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.

References

  1. Macpherson, A. J. & Uhr, T. Compartmentalization of the mucosal immune responses to commensal intestinal bacteria. Ann. NY Acad. Sci. 1029, 36–43 (2004)

    ADS  CAS  Article  Google Scholar 

  2. Hooper, L. V. & Gordon, J. I. Commensal host-bacterial relationships in the gut. Science 292, 1115–1118 (2001)

    ADS  CAS  Article  Google Scholar 

  3. Hooper, L. V., Midtvedt, T. & Gordon, J. I. How host-microbial interactions shape the nutrient environment of the mammalian intestine. Annu. Rev. Nutr. 22, 283–307 (2002)

    CAS  Article  Google Scholar 

  4. Hooper, L. V. et al. Molecular analysis of commensal host-microbial relationships in the intestine. Science 291, 881–884 (2001)

    ADS  CAS  Article  Google Scholar 

  5. Rakoff-Nahoum, S., Paglino, J., Eslami-Varzaneh, F., Edberg, S. & Medzhitov, R. Recognition of commensal microflora by toll-like receptors is required for intestinal homeostasis. Cell 118, 229–241 (2004)

    CAS  Article  Google Scholar 

  6. Mazmanian, S. K., Liu, C. H., Tzianabos, A. O. & Kasper, D. L. An immunomodulatory molecule of symbiotic bacteria directs maturation of the host immune system. Cell 122, 107–118 (2005)

    CAS  Article  Google Scholar 

  7. Balfour Sartor, R. Bacteria in Crohn’s disease: mechanisms of inflammation and therapeutic implications. J. Clin. Gastroenterol. 41 (suppl. 1). S37–S43 (2007)

    Article  Google Scholar 

  8. Schulz, O. et al. Intestinal CD103+, but not CX3CR1+, antigen sampling cells migrate in lymph and serve classical dendritic cell functions. J. Exp. Med. 206, 3101–3114 (2009)

    CAS  Article  Google Scholar 

  9. Macpherson, A. J. & Harris, N. L. Interactions between commensal intestinal bacteria and the immune system. Nature Rev. Immunol. 4, 478–485 (2004)

    CAS  Article  Google Scholar 

  10. Vazquez-Torres, A. et al. Extraintestinal dissemination of Salmonella by CD18-expressing phagocytes. Nature 401, 804–808 (1999)

    ADS  CAS  Article  Google Scholar 

  11. Griffin, A. J. & McSorley, S. J. Development of protective immunity to Salmonella, a mucosal pathogen with a systemic agenda. Mucosal Immunol. 4, 371–382 (2011)

    CAS  Article  Google Scholar 

  12. Hapfelmeier, S. et al. Microbe sampling by mucosal dendritic cells is a discrete, MyD88-independent step in ΔinvG S. Typhimurium colitis. J. Exp. Med. 205, 437–450 (2008)

    CAS  Article  Google Scholar 

  13. Mowat, A. M. Anatomical basis of tolerance and immunity to intestinal antigens. Nature Rev. Immunol. 3, 331–341 (2003)

    CAS  Article  Google Scholar 

  14. Macpherson, A. J. & Uhr, T. Induction of protective IgA by intestinal dendritic cells carrying commensal bacteria. Science 303, 1662–1665 (2004)

    ADS  CAS  Article  Google Scholar 

  15. Bogunovic, M. et al. Origin of the lamina propria dendritic cell network. Immunity 31, 513–525 (2009)

    CAS  Article  Google Scholar 

  16. Varol, C. et al. Intestinal lamina propria dendritic cell subsets have different origin and functions. Immunity 31, 502–512 (2009)

    CAS  Article  Google Scholar 

  17. Jung, S. et al. In vivo depletion of CD11c+ dendritic cells abrogates priming of CD8+ T cells by exogenous cell-associated antigens. Immunity 17, 211–220 (2002)

    CAS  Article  Google Scholar 

  18. Vallon-Eberhard, A., Landsman, L., Yogev, N., Verrier, B. & Jung, S. Transepithelial pathogen uptake into the small intestinal lamina propria. J. Immunol. 176, 2465–2469 (2006)

    CAS  Article  Google Scholar 

  19. Jang, M. H. et al. CCR7 is critically important for migration of dendritic cells in intestinal lamina propria to mesenteric lymph nodes. J. Immunol. 176, 803–810 (2006)

    CAS  Article  Google Scholar 

  20. Worbs, T. et al. Oral tolerance originates in the intestinal immune system and relies on antigen carriage by dendritic cells. J. Exp. Med. 203, 519–527 (2006)

    CAS  Article  Google Scholar 

  21. Varol, C., Zigmond, E. & Jung, S. Securing the immune tightrope: mononuclear phagocytes in the intestinal lamina propria. Nature Rev. Immunol. 10, 415–426 (2010)

    CAS  Article  Google Scholar 

  22. Rivollier, A., He, J., Kole, A., Valatas, V. & Kelsall, B. L. Inflammation switches the differentiation program of Ly6Chi monocytes from antiinflammatory macrophages to inflammatory dendritic cells in the colon. J. Exp. Med. 209, 139–155 (2012)

    CAS  Article  Google Scholar 

  23. Johansson-Lindbom, B. et al. Functional specialization of gut CD103+ dendritic cells in the regulation of tissue-selective T cell homing. J. Exp. Med. 202, 1063–1073 (2005)

    CAS  Article  Google Scholar 

  24. Rydstrom, A. & Wick, M. J. Monocyte recruitment, activation, and function in the gut-associated lymphoid tissue during oral Salmonella infection. J. Immunol. 178, 5789–5801 (2007)

    Article  Google Scholar 

  25. Jung, S. et al. Analysis of fractalkine receptor CX3CR1 function by targeted deletion and green fluorescent protein reporter gene insertion. Mol. Cell. Biol. 20, 4106–4114 (2000)

    CAS  Article  Google Scholar 

  26. Frank, D. N. et al. Molecular-phylogenetic characterization of microbial community imbalances in human inflammatory bowel diseases. Proc. Natl Acad. Sci. USA 104, 13780–13785 (2007)

    ADS  CAS  Article  Google Scholar 

  27. Kaser, A., Zeissig, S. & Blumberg, R. S. Inflammatory bowel disease. Annu. Rev. Immunol. 28, 573–621 (2010)

    CAS  Article  Google Scholar 

  28. Thiennimitr, P., Winter, S. E. & Baumler, A. J. Salmonella, the host and its microbiota. Curr. Opin. Microbiol. 15, 108–114 (2012)

    Article  Google Scholar 

  29. Lupp, C. et al. Host-mediated inflammation disrupts the intestinal microbiota and promotes the overgrowth of Enterobacteriaceae. Cell Host Microbe 2, 119–129 (2007)

    CAS  Article  Google Scholar 

  30. Valdez, Y. et al. Nramp1 expression by dendritic cells modulates inflammatory responses during Salmonella Typhimurium infection. Cell. Microbiol. 10, 1646–1661 (2008)

    CAS  Article  Google Scholar 

  31. Liu, F. & Whitton, J. L. Cutting edge: re-evaluating the in vivo cytokine responses of CD8+ T cells during primary and secondary viral infections. J. Immunol. 174, 5936–5940 (2005)

    CAS  Article  Google Scholar 

  32. Vaishnava, S., Behrendt, C. L., Ismail, A. S., Eckmann, L. & Hooper, L. V. Paneth cells directly sense gut commensals and maintain homeostasis at the intestinal host-microbial interface. Proc. Natl Acad. Sci. USA 105, 20858–20863 (2008)

    ADS  CAS  Article  Google Scholar 

  33. Napolitano, L. M., Koruda, M. J., Meyer, A. A. & Baker, C. C. The impact of femur fracture with associated soft tissue injury on immune function and intestinal permeability. Shock 5, 202–207 (1996)

    CAS  Article  Google Scholar 

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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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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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The authors declare no competing financial interests.

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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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