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Identification of an innate T helper type 17 response to intestinal bacterial pathogens

Nature Medicine volume 17, pages 837–844 (2011)Cite this article

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Abstract

Interleukin 17 (IL-17) is a central cytokine implicated in inflammation and antimicrobial defense. After infection, both innate and adaptive IL-17 responses have been reported, but the type of cells involved in innate IL-17 induction, as well as their contribution to in vivo responses, are poorly understood. Here we found that Citrobacter and Salmonella infection triggered early IL-17 production, which was crucial for host defense and was mediated by CD4+ T helper cells. Enteric innate T helper type 17 (iTH17) responses occurred principally in the cecum, were dependent on the Nod-like receptors Nod1 and Nod2, required IL-6 induction and were associated with a decrease in mucosal CD103+ dendritic cells. Moreover, imprinting by the intestinal microbiota was fully required for the generation of iTH17 responses. Together, these results identify the Nod-iTH17 axis as a central element in controlling enteric pathogens, which may implicate Nod-driven iTH17 responses in the development of inflammatory bowel diseases.

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Figure 1: Nod1 and Nod2 differentially modulate early and late inflammation during C. rodentium-induced colitis.
Figure 2: Early IL-17 responses during C. rodentium–induced colitis are Nod1 and Nod2 dependent.
Figure 3: Acute IL-17 responses during S. typhimurium-induced colitis are dependent on hematopoietic and non-hematopoietic Nod1 and Nod2.
Figure 4: IL-6 expression during C. rodentium- and S. typhimurium (SL1344)-induced colitis are Nod1 and Nod2 dependent.
Figure 5: IL-6 expression during the acute phase of infectious colitis is crucial for TH17 development.
Figure 6: Early TH17 cells express memory surface markers and require microbiota for activation.

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Acknowledgements

We thank L. Morikawa for help with preparing histological sections and K. Banks for help with animal experimentation. We also are very grateful to those individuals who volunteered for intestinal biopsies. Nod2−/− mice were provided by J.P. Hugot at Institut National de la Santé et de la Recherche Médicale U843. C. rodentium strain DBS100 was provided by B. Finlay at the University of British Columbia. This work was supported by a grant from the Crohn's and Colitis Foundation of Canada to S.E.G., a Crohn's and Colitis Foundation of Canada and a Canadian Institute of Health Research operating grant (480142) to D.J.P. and by a Canadian Institutes of Health Research grant (HET-85518) and an Ontario HIV Treatment Network grant (OGB-G123) to R.K. K.G. was supported by a Canadian Association of Gastroenterology/Canadian Institutes of Health Research postdoctoral research award, and S.J.R. was supported by a Fonds de la Recherche en Santé du Québec graduate scholarship.

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Author notes

  1. Kaoru Geddes and Stephen J Rubino: These authors contributed equally to this work.

Authors and Affiliations

  1. Department of Immunology, University of Toronto, Toronto, Ontario, Canada

    Kaoru Geddes, Joao G Magalhaes, Lionel Le Bourhis, Joon Ho Cho, Susan J Robertson, Rupert Kaul & Dana J Philpott

  2. Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, Ontario, Canada

    Stephen J Rubino & Stephen E Girardin

  3. Department of Laboratory Medicine, St. Michael's Hospital, Toronto, Ontario, Canada

    Catherine Streutker

  4. Department of Medicine, University of Toronto, Toronto, Ontario, Canada

    Connie J Kim & Rupert Kaul

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Contributions

K.G. and S.J.R. designed and performed all experiments and wrote the manuscript. J.G.M. designed and performed mouse experiments. C.S. performed pathological scoring analysis. L.L.B. generated the Nod1−/−Nod2−/− mice. J.H.C. and S.J.R. performed microbiota analysis. C.J.K. and R.K. provided human colonic samples. D.J.P. and S.E.G. directed the research and wrote the manuscript.

Corresponding authors

Correspondence to Dana J Philpott or Stephen E Girardin.

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The authors declare no competing financial interests.

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Geddes, K., Rubino, S., Magalhaes, J. et al. Identification of an innate T helper type 17 response to intestinal bacterial pathogens. Nat Med 17, 837–844 (2011). https://doi.org/10.1038/nm.2391

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