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Abstract

Inflammation is a beneficial host response to infection but can contribute to inflammatory disease if unregulated. The Th17 lineage of T helper (Th) cells can cause severe human inflammatory diseases. These cells exhibit both instability (they can cease to express their signature cytokine, IL-17A)1 and plasticity (they can start expressing cytokines typical of other lineages)1,2 upon in vitro re-stimulation. However, technical limitations have prevented the transcriptional profiling of pre- and post-conversion Th17 cells ex vivo during immune responses. Thus, it is unknown whether Th17 cell plasticity merely reflects change in expression of a few cytokines, or if Th17 cells physiologically undergo global genetic reprogramming driving their conversion from one T helper cell type to another, a process known as transdifferentiation3,4. Furthermore, although Th17 cell instability/plasticity has been associated with pathogenicity1,2,5, it is unknown whether this could present a therapeutic opportunity, whereby formerly pathogenic Th17 cells could adopt an anti-inflammatory fate. Here we used two new fate-mapping mouse models to track Th17 cells during immune responses to show that CD4+ T cells that formerly expressed IL-17A go on to acquire an anti-inflammatory phenotype. The transdifferentiation of Th17 into regulatory T cells was illustrated by a change in their signature transcriptional profile and the acquisition of potent regulatory capacity. Comparisons of the transcriptional profiles of pre- and post-conversion Th17 cells also revealed a role for canonical TGF-β signalling and consequently for the aryl hydrocarbon receptor (AhR) in conversion. Thus, Th17 cells transdifferentiate into regulatory cells, and contribute to the resolution of inflammation. Our data suggest that Th17 cell instability and plasticity is a therapeutic opportunity for inflammatory diseases.

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Change history

  • 08 July 2015

    Minor changes were made to the Acknowledgements, and the GEO accession code was added.

Accessions

Primary accessions

Gene Expression Omnibus

Data deposits

The RNA sequencing data have been deposited in the Gene Expression Omnibus (GEO) database under the accession number GSE68242.

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Acknowledgements

The authors would like to thank C. Lieber, P. Musco, E. Hughes-Picard and J. Alderman for expert administrative assistance. J. Stein, L. Evangelisti and C. Hughes for generating the IL-17A IRES-eGFP-CRE-ERT2 constructs, embryonic stem cells and chimaeric mice, respectively. We thank E. Baiocchi for remote key support. LXG is supported by grants K01ES025434 from NIH/BD2K and P20 COBRE GM103457 from NIH/NIGMS. E.E. was supported by the DFG (EXC 257 NeuroCure and SFB633) and by the Crohn’s & Colitis Foundation of America (#311143). N.G. is supported by the Dr. Keith Landesman Memorial Fellowship of the Cancer Research Institute. S.H. is supported by the DFG (HU1714/3) and by Ernst Jung-Stiftung Hamburg and has an endowed Hofschneider-Professorship from the Stiftung Experimentelle Biomedizin. This work was supported, by the Howard Hughes Medical Institute, by Cariplo foundation (2013-0937 to J.G. and R.A.F.), by the AbbVie-Yale Collaboration (R.A.F.) and by the Francis Crick Institute (B.S.).

Author information

Author notes

    • Maria Carolina Amezcua Vesely
    •  & Andrea Iseppon

    These authors contributed equally to this work.

    • Samuel Huber
    •  & Richard A. Flavell

    These authors jointly supervised this work.

Affiliations

  1. Department of Immunobiology, School of Medicine, Yale University, New Haven, 06520, USA

    • Nicola Gagliani
    • , Maria Carolina Amezcua Vesely
    • , Andrea Iseppon
    • , Hao Xu
    • , Noah W. Palm
    • , Marcel R. de Zoete
    • , Paula Licona-Limón
    • , Ricardo S. Paiva
    •  & Richard A. Flavell
  2. Medizinische Klinik und Poliklinik, Universitätsklinikum Hamburg-Eppendorf, Hamburg 20246, Germany

    • Leonie Brockmann
    •  & Samuel Huber
  3. Howard Hughes Medical Institute, Yale University School of Medicine, New Haven, Connecticut 06520, USA

    • Marcel R. de Zoete
    •  & Richard A. Flavell
  4. University of Hawaii Cancer Center, Manoa 96813, USA

    • Travers Ching
    •  & Lana X. Garmire
  5. Department of Pathology, University of Alabama at Birmingham, Birmingham, Alabama 35294, USA

    • Casey Weaver
  6. Department of Biomedical Engineering, Yale University, New Haven, 06520, USA

    • Xiaoyuan Zi
    •  & Rong Fan
  7. Department of Genetics, Yale University School of Medicine, New Haven, Connecticut 06520, USA

    • Xinghua Pan
  8. Howard Hughes Medical Institute and Department of Pathology, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts 02114, USA

    • Matthew J. Cotton
    • , Yotam Drier
    •  & Bradley Bernstein
  9. Istituto Nazionale di Genetica Molecolare “Romeo ed Enrica Invernizzi”, Milan 20122, Italy

    • Jens Geginat
  10. Division of Molecular Immunology, MRC National Institute for Medical Research, Mill Hill, London NW7 1AA, UK

    • Brigitta Stockinger
  11. Immunology Institute, Mount Sinai School of Medicine, Icahn Medical Institute, New York, New York, USA

    • Enric Esplugues
  12. Departamento de Biología Celular y del Desarrollo, Instituto de Fisiología Celular, Universidad Nacional Autónoma de México, D.F. México 04510, México (P.L.-L.); Department of Cell Biology, Second Military Medical University, Shanghai 200433, China (X.Z.)

    • Paula Licona-Limón
    •  & Xiaoyuan Zi

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Contributions

N.G. designed and performed the experiments, analysed the data and wrote the manuscript. M.C.A.V., A.I., H.X. and L.B. performed the experiments and analysed the data. N.W.P. and M.R.d.Z. optimized the isolation of intestinal cells. P.L-L. provided the expertise and supervised the experiments with N. brasiliensis. T.C. performed bioinformatics analysis and L.X.G. supervised the bioinformatics analysis. C.W. provided the IL-10Thy1.1 mice. X.Z., X.P., R.F. performed and supervised the extraction, amplification and library preparation for RNA sequencing. M.J.C., Y.D. and B.B. assisted with expression profiling and data analysis. M.R.d.Z., P.L.-L., J.G., R.S.P. and E.E. discussed and interpreted the results. N.W.P. discussed and interpreted the results and helped in writing the paper. B.S. provided the IL-17A Cre mice and the protocol for the intracellular staining. R.A.F. and S.H. wrote the manuscript and supervised the project.

Competing interests

The authors declare no competing financial interests.

Corresponding authors

Correspondence to Samuel Huber or Richard A. Flavell.

Extended data

Supplementary information

Excel files

  1. 1.

    Supplementary Table 1

    This table contains the list of Th17 related genes. This list was used to generate the cluster analysis shown in Figure 3a.

  2. 2.

    Supplementary Table 2

    This table contains the list of cytokine genes used to generate the cluster analysis shown in Figure 3b.

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DOI

https://doi.org/10.1038/nature14452

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