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