Th17 cells transdifferentiate into regulatory T cells during resolution of inflammation

Nicola Gagliani, Maria Carolina Amezcua Vesely, Andrea Iseppon, Leonie Brockmann, Hao Xu, Noah W. Palm, Marcel R. de Zoete, Paula Licona-Limón, Ricardo S. Paiva, Travers Ching, Casey Weaver, Xiaoyuan Zi, Xinghua Pan, Rong Fan, Lana X. Garmire, Matthew J. Cotton, Yotam Drier, Bradley Bernstein, Jens Geginat, Brigitta Stockinger, Enric Esplugues, Samuel Huber () and Richard A. Flavell ()
Additional contact information
Nicola Gagliani: School of Medicine, Yale University
Maria Carolina Amezcua Vesely: School of Medicine, Yale University
Andrea Iseppon: School of Medicine, Yale University
Leonie Brockmann: Medizinische Klinik und Poliklinik, Universitätsklinikum Hamburg-Eppendorf
Hao Xu: School of Medicine, Yale University
Noah W. Palm: School of Medicine, Yale University
Marcel R. de Zoete: School of Medicine, Yale University
Paula Licona-Limón: School of Medicine, Yale University
Ricardo S. Paiva: School of Medicine, Yale University
Travers Ching: University of Hawaii Cancer Center
Casey Weaver: University of Alabama at Birmingham
Xiaoyuan Zi: Yale University
Xinghua Pan: Yale University School of Medicine
Rong Fan: Yale University
Lana X. Garmire: University of Hawaii Cancer Center
Matthew J. Cotton: Massachusetts General Hospital and Harvard Medical School
Yotam Drier: Massachusetts General Hospital and Harvard Medical School
Bradley Bernstein: Massachusetts General Hospital and Harvard Medical School
Jens Geginat: Istituto Nazionale di Genetica Molecolare “Romeo ed Enrica Invernizzi”
Brigitta Stockinger: MRC National Institute for Medical Research
Enric Esplugues: Immunology Institute, Mount Sinai School of Medicine, Icahn Medical Institute
Samuel Huber: Medizinische Klinik und Poliklinik, Universitätsklinikum Hamburg-Eppendorf
Richard A. Flavell: School of Medicine, Yale University

Nature, 2015, vol. 523, issue 7559, 221-225

Abstract: 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.

Date: 2015
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DOI: 10.1038/nature14452

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