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RORγt and commensal microflora are required for the differentiation of mucosal interleukin 22–producing NKp46+ cells

Nature Immunology volume 10, pages 83–91 (2009)Cite this article

Abstract

The mucosal immune system of the intestine is separated from a vast array of microbes by a single layer of epithelial cells. Cues from the commensal microflora are needed to maintain epithelial homeostasis, but the molecular and cellular identities of these cues are unclear. Here we provide evidence that signals from the commensal microflora contribute to the differentiation of a lymphocyte population coexpressing stimulatory natural killer cell receptors and the transcription factor RORγt that produced interleukin 22 (IL-22). The emergence of these IL-22-producing RORγthiNKp46+NK1.1int cells depended on RORγt expression, which indicated that these cells may have been derived from lymphoid tissue–inducer cells. IL-22 released by these cells promoted the production of antimicrobial molecules important in the maintenance of mucosal homeostasis.

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Figure 1: Lamina propria NKp46+ cells have an immature phenotype.
Figure 2: Mucosal NKp46+ cells localize in cryptopatches.
Figure 3: NKp46+ cells of the lamina propria express RORγt.
Figure 4: Mucosal NKp46+ cells have only weak NK cell effector functions.
Figure 5: Lamina propria RORγthiNKp46+NK1.1int cells produce IL-22.
Figure 6: Germ-free mice lack IL-22-producing RORγthiNKp46+NK1.1int cells.

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Acknowledgements

We thank M. Kist for support; M. Lucas, H. Pircher, W. Schachterle and C. Vonarbourg for critical comments on the manuscript; M. Schnare for discussions; K. Geiger and M. Follo for cell sorting; D. Littman (New York University) for Rorc(γt)GFP/+ mice; B. Stockinger (National Institute for Medical Research Mill Hill) for support and reagents; M. Kopf (Swiss Federal Institute of Technology Zürich) for Il6−/− mice on a B6 background; J.-C. Renauld (Ludwig Institute for Cancer Research Brussels) for anti-IL-22; and N. Goeppert for technical assistance. Supported by Deutsche Forschungsgemeinschaft (Di 764/2-2, GRK1104 (A.M.) and SFB620).

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Author notes

  1. Viet L Bui and Arthur Mortha: These authors contributed equally to this work.

Authors and Affiliations

  1. Institute of Medical Microbiology and Hygiene, University of Freiburg, Freiburg, 79104, Germany

    Stephanie L Sanos, Viet L Bui, Arthur Mortha, Karin Oberle, Charlotte Heners & Andreas Diefenbach

  2. The Kimmel Center for Biology and Medicine at the Skirball Institute for Biomolecular Medicine, New York University School of Medicine, New York, 10016, New York, USA

    Stephanie L Sanos, Viet L Bui & Andreas Diefenbach

  3. Max-Planck Institute of Immunobiology, Freiburg, 79108, Germany

    Caroline Johner

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Contributions

S.L.S., V.L.B., A.M., K.O. and C.H. did and analyzed the experiments; C.J. generated and provided the germ-free mice and contributed to the experimental design; and A.D. and S.L.S. designed the experiments and wrote the paper.

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Correspondence to Andreas Diefenbach.

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Sanos, S., Bui, V., Mortha, A. et al. RORγt and commensal microflora are required for the differentiation of mucosal interleukin 22–producing NKp46+ cells. Nat Immunol 10, 83–91 (2009). https://doi.org/10.1038/ni.1684

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