TH17 cells transdifferentiate into regulatory T cells uring 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 StockingerEnric Esplugues, Samuel Huber, Richard A. Flavell*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

606 Scopus citations

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 pathogenicTH17 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 antiinflammatory 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 postconversion 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.

Original languageAmerican English
Pages (from-to)221-225
Number of pages5
JournalNature
Volume523
Issue number7559
DOIs
StatePublished - 9 Jul 2015
Externally publishedYes

Bibliographical note

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© 2015 Macmillan Publishers Limited. All rights reserved.

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