Elsevier

Mucosal Immunology

Volume 9, Issue 2, March 2016, Pages 444-457
Mucosal Immunology

Article
Foxp3+ T cells expressing RORγt represent a stable regulatory T-cell effector lineage with enhanced suppressive capacity during intestinal inflammation

https://doi.org/10.1038/mi.2015.74Get rights and content
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Abstract

Foxp3 (forkhead box P3 transcription factor)-expressing regulatory T cells (Tregs) are essential for immunological tolerance, best illustrated by uncontrolled effector T-cell responses and autoimmunity upon loss of Foxp3 expression. Tregs can adopt specific effector phenotypes upon activation, reflecting the diversity of functional demands in the different tissues of the body. Here, we report that Foxp3+CD4+ T cells coexpressing retinoic acid-related orphan receptor-γt (RORγt), the master transcription factor for T helper type 17 (Th17) cells, represent a stable effector Treg lineage. Transcriptomic and epigenetic profiling revealed that Foxp3+RORγt+ T cells display signatures of both Tregs and Th17 cells, although the degree of similarity was higher to Foxp3+RORγt Tregs than to Foxp3RORγt+ T cells. Importantly, Foxp3+RORγt+ T cells were significantly demethylated at Treg-specific epigenetic signature genes such as Foxp3, Ctla-4, Gitr, Eos, and Helios, suggesting that these cells have a stable regulatory rather than inflammatory function. Indeed, adoptive transfer of Foxp3+RORγt+ T cells in the T-cell transfer colitis model confirmed their Treg function and lineage stability in vivo, and revealed an enhanced suppressive capacity as compared with Foxp3+RORγt Tregs. Thus, our data suggest that RORγt expression in Tregs contributes to an optimal suppressive capacity during gut-specific immune responses, rendering Foxp3+RORγt+ T cells as an important effector Treg subset in the intestinal system.

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Published online: 26 August 2015

SUPPLEMENTARY MATERIAL is linked to the online version of the paper at

B-H Yang, S Hagemann, S Floess, J Huehn and M Lochner: These authors contributed equally to this work.

Supplementary information The online version of this article (doi:10.1038/mi.2015.74) contains supplementary material, which is available to authorized users.