Th17 cells transdifferentiate into regulatory T cells during resolution of inflammation

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 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.

Harnessing the plasticity of CD4+ T cells to treat immune-mediated disease

“…The blended phenotype of 'T H 2/T H 1' cells that co-express IL-4 and IFNγ (as well as GATA3 and T-bet) or the induction of IL-10 expression by T H 1 cells can reduce the collateral damage associated with excessive T H 1 cell responses 20,35,42,195 . Extinction of pathogenic immune responses, such as those driven by T H 17 cells, is aided by the conversion of T H 17 cells into IL-10-producing T R 1 cells 41,44,[196][197][198] . T helper cell transitions can also alter chemokine receptor expression and divert pathogenic cells to new tissues, redu cing inflammation at the primary site 196,197 .…”

“…TGFβ is crucial for the conversion of T H 17 cells towards a regulatory phenotype through the promotion of forkhead box P3 (FOXP3) or IL-10 expression [39][40][41] . In addition, the pleiotropic cytokine IL-27 can induce IL-10 expression by various inflammatory subsets to promote regulatory functions, as well as induce the generation of type 1 regulatory T (T R 1) cells de novo [42][43][44] .…”

Regulation of the Immune Response by TGF-β: From Conception to Autoimmunity and Infection

“…Such opposing effects of TGF-b on Th17-associated cytokines may contribute to the regulatory or pathogenic functions of these cells. Intriguingly, Th17 cells transdifferentiate into regulatory T cells in a TGF-b-and aryl hydrocarbon receptor (AhR)-dependent manner at the resolution of inflammation (Gagliani et al 2015), thus further showing the role of TGF-b in the plasticity and switch between immunity and tolerance.…”

Microbiota, regulatory T cell subsets, and allergic disorders

“…It should be noted that during the resolution of an in ammation, ROR(γt) + 17 can also trans-differentiate into Foxp3 − regulatory T cells expressing the anti-in ammatory cytokine IL-10 [71]. Only few ROR(γt) + Foxp3 + Tregs are directly generated from ex 17 cells [67,71].…”