Th17 cells transdifferentiate into regulatory T cells during resolution of inflammation

By N. Gagliani, M. A. Vesely, A. Iseppon, L. Brockmann, Hao Xu, Noah W. Palm, Marcel R. de Zoete, P. Licona-Limón, R. Paiva, Travers Ching and 13 more. Nature, 2015

766 citations recorded by the source corpus.

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.

Subfields: Immunology

View Paper: https://www.semanticscholar.org/paper/de68cf1ddb39bd9250fa626f27ac58558d58762f

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In Immunology

Citations in the corpus

Single-cell Genomics Unveils Critical Regulators of Th17 cell Pathogenicity (2015, neutral): “Th17 cell signature (Gagliani et al., 2015)(Figure 4C, Table S2); (2) correlation with the inflammatory CNS derived Th17 cells in vivo (Figure 2A); (3) enrichment of genes in the co-variation modules (rows of Figure 4B) for immune response genes (using MSigDB (Liberzon et al.”
The Balance of Th17 versus Treg Cells in Autoimmunity (2018, background): “An experiment using lineage-tracing mice with Th17-mediated colitis revealed that Th17 cells acquire the signature transcriptional profile and potent suppressive functions of Tr1 cells [107].”
Monocyte-Macrophages and T Cells in Atherosclerosis (2017, neutral): “For example, after bacterial andworm infections in fate-mapping reportermice, Th17 cells were shown to transdifferentiate into FoxP3 Treg cells as inflammation resolved (Gagliani et al., 2015).”
Regulation of the immune response by the aryl hydrocarbon receptor (2018, background): “Thus, considering reports on the AhR-dependent differentiation of Th17 cells into IL-10-producing Tr1-like cells (Gagliani et al., 2015), AhR may be associated with plastic Th17 cell populations that require additional signals to complete their differentiation into fully pathogenic Th17 cells or reg”