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RORγt+ innate lymphoid cells regulate intestinal homeostasis by integrating negative signals from the symbiotic microbiota

Nature Immunology volume 12, pages 320–326 (2011)Cite this article

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Abstract

Lymphoid cells that express the nuclear hormone receptor RORγt are involved in containment of the large intestinal microbiota and defense against pathogens through the production of interleukin 17 (IL-17) and IL-22. They include adaptive IL-17-producing helper T cells (TH17 cells), as well as innate lymphoid cells (ILCs) such as lymphoid tissue–inducer (LTi) cells and IL-22-producing NKp46+ cells. Here we show that in contrast to TH17 cells, both types of RORγt+ ILCs constitutively produced most of the intestinal IL-22 and that the symbiotic microbiota repressed this function through epithelial expression of IL-25. This function was greater in the absence of adaptive immunity and was fully restored and required after epithelial damage, which demonstrates a central role for RORγt+ ILCs in intestinal homeostasis. Our data identify a finely tuned equilibrium among intestinal symbionts, adaptive immunity and RORγt+ ILCs.

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Figure 1: RORγt+ ILCs are the main producers of IL-22 in the intestine.
Figure 2: The production of proinflammatory cytokines by RORγt+ ILCs.
Figure 3: The microbiota represses IL-22 production by RORγt+ ILCs.
Figure 4: The microbiota represses the activity of RORγt+ ILCs via IL-25.
Figure 5: Adaptive immunity represses the activity of RORγt+ ILCs.
Figure 6: Epithelial damage de-represses the activity of RORγt+ ILCs.
Figure 7: The activity of RORγt+ ILCs is required for protection and recovery from colitis.

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  • 27 February 2011

    In the version of this article initially published online, the first sentence of the abstract was incorrect. This sentence should begin “Lymphoid cells that express the nuclear hormone receptor RORγt....” The error has been corrected for the print, PDF and HTML versions of this article.

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Acknowledgements

We thank the members of the Lymphoid Tissue Development Unit for discussions and critical reading of the manuscript; L. Polomack for technical assistance; J. Perez and E. Maranghi for work on germ-free mice; and B. Ryffel for p19-deficient mice. Supported by the Institut Pasteur, the Mairie de Paris, the Agence Nationale de la Recherche, the European Commission, Deutsche Forschungsgemeinschaft (M.L.) and the Schlumberger Foundation (M.L.).

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Authors and Affiliations

  1. Institut Pasteur, Lymphoid Tissue Development Unit, Paris, France

    Shinichiro Sawa, Matthias Lochner, Sophie Dulauroy & Gérard Eberl

  2. Centre National de la Recherche Scientifique, Unités de Recherche Associées 1961, Paris, France

    Shinichiro Sawa, Matthias Lochner, Sophie Dulauroy & Gérard Eberl

  3. Institute of Infection Immunology, TWINCORE, Centre for Experimental and Clinical Infection Research (joint venture of the Medical School Hannover and the Helmholtz Centre for Infection Research), Hannover, Germany

    Matthias Lochner

  4. Institut Pasteur, Innate Immunity Unit, Paris, France

    Naoko Satoh-Takayama & James P Di Santo

  5. Institut National de la Santé et de la Recherche Médicale U668, Paris, France

    Naoko Satoh-Takayama & James P Di Santo

  6. Institut Pasteur, Animalerie Centrale, Paris, France

    Marion Bérard

  7. Merck Research Laboratories, DNAX Discovery Research, Palo Alto, California, USA

    Melanie Kleinschek & Daniel Cua

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Contributions

S.S. and G.E. designed the study and wrote the manuscript; S.S. did most of the experimental work; M.L. contributed to the analysis of T cells and DSS-mediated colitis; N.S.-T. contributed to the analysis of NKp46+ ILCs; S.D. did laser-capture microdissection; M.B. generated germ-free mice; M.K. and D.C. generated and provided IL-25-deficient mice; and J.P.D.S. contributed to data analysis and manuscript writing.

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Correspondence to Gérard Eberl.

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D.C. and M.K. are employees of Merck Research Laboratories, DNAX Discovery Research.

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Sawa, S., Lochner, M., Satoh-Takayama, N. et al. RORγt+ innate lymphoid cells regulate intestinal homeostasis by integrating negative signals from the symbiotic microbiota. Nat Immunol 12, 320–326 (2011). https://doi.org/10.1038/ni.2002

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