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A T-bet gradient controls the fate and function of CCR6−RORγt+ innate lymphoid cells

Nature volume 494, pages 261–265 (2013)Cite this article

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Abstract

At mucosal surfaces, the immune system should not initiate inflammatory immune responses to the plethora of antigens constantly present in the environment, but should remain poised to unleash a potent assault on intestinal pathogens. The transcriptional programs and regulatory factors required for immune cells to switch from homeostatic (often tissue-protective) function1 to potent antimicrobial immunity are poorly defined. Mucosal retinoic-acid-receptor-related orphan receptor-γt-positive (RORγt+) innate lymphoid cells (ILCs) are emerging as an important innate lymphocyte population required for immunity to intestinal infections2. Various subsets of RORγt+ ILCs have been described3,4,5,6,7,8 but the transcriptional programs controlling their specification and fate remain largely unknown. Here we provide evidence that the transcription factor T-bet determines the fate of a distinct lineage of CCR6−RORγt+ ILCs. Postnatally emerging CCR6−RORγt+ ILCs upregulated T-bet and this was controlled by cues from the commensal microbiota and interleukin-23 (IL-23). In contrast, CCR6+RORγt+ ILCs, which arise earlier during ontogeny, did not express T-bet. T-bet instructed the expression of T-bet target genes such as interferon-γ (IFN-γ) and of the natural cytotoxicity receptor NKp46. Mice genetically lacking T-bet showed normal development of CCR6−RORγt+ ILCs, but they could not differentiate into NKp46-expressing RORγt+ ILCs (that is, IL-22-producing natural killer (NK-22) cells)3,9 and failed to produce IFN-γ. The production of IFN-γ by T-bet-expressing CCR6−RORγt+ ILCs was essential for the release of mucus-forming glycoproteins required to protect the epithelial barrier during Salmonella enterica infection10,11. Salmonella infection also causes severe enterocolitis that is at least partly driven by IFN-γ12. Mice deficient for T-bet or depleted of ILCs developed only mild enterocolitis. Thus, graded expression of T-bet in CCR6−RORγt+ ILCs facilitates the differentiation of IFN-γ-producing CCR6−RORγt+ ILCs required to protect the epithelial barrier against Salmonella infections. Co-expression of T-bet and RORγt, which is also found in subsets of IL-17-producing T-helper (TH17) cells13, may be an evolutionarily conserved transcriptional program that originally developed as part of the innate defence against infections but that also confers an increased risk of immune-mediated pathology.

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Figure 1: CCR6−RORγt+ ILCs express T-bet.
Figure 2: CCR6−T-bet+RORγt+ ILCs and CCR6+T-bet−RORγt+ ILCs are separate ILC lineages.
Figure 3: Microbiota and IL-23 control T-bet expression by CCR6−RORγt+ ILCs.
Figure 4: IFN-γ-producing NKp46+CCR6−T-bet+RORγt+ ILCs control mucus release and inflammation following Salmonella infection.

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Acknowledgements

We thank G. Häcker for support, the members of the Diefenbach laboratory for valuable discussions, and C. A. Connor for comments on the manuscript. We are grateful to M. Follo, K. Geiger and J. Bodinek-Wersing for cell sorting. The work was supported by the Deutsche Forschungsgemeinschaft (SFB620/A14 to A.D. and TA436/2-1 to Y.T.), the German Federal Ministry of Education and Research (BMBF 01 EO 0803 to A.D. and Y.T.), an EFSD/Lilly grant (to Y.T.), a European Research Council Grant (to A.D.), a CCI Walter-Hitzig-Fellowship (to V.S.), an EMBO Long Term Fellowship (ALTF 508-2011 to A.L.C.) and the FP6 Marie Curie Research Training Network (grant MRTN-CT-2004-005632 (IMDEMI) to A.W.).

Author information

Author notes

  1. Yakup Tanriver and Andreas Diefenbach: These authors contributed equally to this work.

Authors and Affiliations

  1. Institute of Medical Microbiology and Hygiene (IMMH), University of Freiburg, Hermann-Herder-Strasse 11, D-79104 Freiburg, Germany,

    Christoph S. N. Klose, Elina A. Kiss, Vera Schwierzeck, Karolina Ebert, Thomas Hoyler, Yannick d’Hargues, Nathalie Göppert, Yakup Tanriver & Andreas Diefenbach

  2. Centre of Chronic Immunodeficiency (CCI), University Medical Center Freiburg and University of Freiburg, Breisacher Strasse 117, D-79106 Freiburg, Germany,

    Vera Schwierzeck, Yakup Tanriver & Andreas Diefenbach

  3. Renal Division, University of Freiburg Medical Centre, Hugstetter Strasse 55, D-79106 Freiburg, Germany,

    Karolina Ebert, Yannick d’Hargues & Yakup Tanriver

  4. Institute of Molecular Medicine, University of Mainz, Obere Zahlbacher Strasse 67, D-55131 Mainz, Germany,

    Andrew L. Croxford & Ari Waisman

  5. Institute of Experimental Immunology, Neuroimmunology, University of Zürich, CH-8006 Zürich, Switzerland,

    Andrew L. Croxford

  6. Centre for Biological Signalling Studies (BIOSS), University of Freiburg, Schänzlestrasse 18, D-79104 Freiburg, Germany,

    Andreas Diefenbach

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Contributions

C.S.N.K. carried out most of the experiments and analysed data, E.A.K. performed infection experiments, histology and immunofluorescence staining, V.S. carried out the analysis of microbial communities, K.E. and N.G. contributed to the infection experiments, T.H. contributed to the analysis of lymphoid organogenesis, Y.d’H. carried out immunofluorescence staining, and A.L.C. and A.W. generated and provided IL-17f–creTg mice. A.D. and Y.T. designed the study, coordinated the experimental work and analysed data. A.D. directed the research and wrote the manuscript with input from co-authors.

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Correspondence to Andreas Diefenbach.

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Klose, C., Kiss, E., Schwierzeck, V. et al. A T-bet gradient controls the fate and function of CCR6−RORγt+ innate lymphoid cells. Nature 494, 261–265 (2013). https://doi.org/10.1038/nature11813

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