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Nature. 2015 Jul 9;523(7559):221-5. doi: 10.1038/nature14452. Epub 2015 Apr 29.

Th17 cells transdifferentiate into regulatory T cells during resolution of inflammation.

Author information

1
Department of Immunobiology, School of Medicine, Yale University, New Haven, 06520, USA.
2
Medizinische Klinik und Poliklinik, Universitätsklinikum Hamburg-Eppendorf, Hamburg 20246, Germany.
3
1] Department of Immunobiology, School of Medicine, Yale University, New Haven, 06520, USA [2] Howard Hughes Medical Institute, Yale University School of Medicine, New Haven, Connecticut 06520, USA.
4
1] Department of Immunobiology, School of Medicine, Yale University, New Haven, 06520, USA [2] 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.).
5
University of Hawaii Cancer Center, Manoa 96813, USA.
6
Department of Pathology, University of Alabama at Birmingham, Birmingham, Alabama 35294, USA.
7
1] Department of Biomedical Engineering, Yale University, New Haven, 06520, USA [2] 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.).
8
Department of Genetics, Yale University School of Medicine, New Haven, Connecticut 06520, USA.
9
Department of Biomedical Engineering, Yale University, New Haven, 06520, USA.
10
Howard Hughes Medical Institute and Department of Pathology, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts 02114, USA.
11
Istituto Nazionale di Genetica Molecolare "Romeo ed Enrica Invernizzi", Milan 20122, Italy.
12
Division of Molecular Immunology, MRC National Institute for Medical Research, Mill Hill, London NW7 1AA, UK.
13
Immunology Institute, Mount Sinai School of Medicine, Icahn Medical Institute, New York, New York, USA.

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) and plasticity (they can start expressing cytokines typical of other lineages) 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 transdifferentiation. Furthermore, although Th17 cell instability/plasticity has been associated with pathogenicity, 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.

Comment in

PMID:
25924064
PMCID:
PMC4498984
DOI:
10.1038/nature14452
[Indexed for MEDLINE]
Free PMC Article

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