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Genome-wide DNA-methylation landscape defines specialization of regulatory T cells in tissues

A Corrigendum to this article was published on 16 November 2017

Abstract

Regulatory T cells (Treg cells) perform two distinct functions: they maintain self-tolerance, and they support organ homeostasis by differentiating into specialized tissue Treg cells. We found that epigenetic modifications defined the molecular characteristics of tissue Treg cells. Tagmentation-based whole-genome bisulfite sequencing revealed more than 11,000 regions that were methylated differentially in pairwise comparisons of tissue Treg cell populations and lymphoid T cells. Similarities in the epigenetic landscape led to the identification of a common tissue Treg cell population that was present in many organs and was characterized by gain and loss of DNA methylation that included many gene sites associated with the TH2 subset of helper T cells, such as the gene encoding cytokine IL-33 receptor ST2, as well as the production of tissue-regenerative factors. Furthermore, the ST2-expressing population was dependent on the transcriptional regulator BATF and could be expanded by IL-33. Thus, tissue Treg cells integrate multiple waves of epigenetic reprogramming that define their tissue-restricted specialization.

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Figure 1: DNA-methylome analysis of tissue-resident Treg cells.
Figure 2: Transcriptome analysis of tissue-resident Treg cells and correlation with the epigenetic data set.
Figure 3: Methylation changes of a Treg cell–specific epigenetic signature.
Figure 4: Identification of epigenetic and transcriptional changes in tissue-resident Treg cells.
Figure 5: Confirmation of the common tissue Treg cell signature and identification of tissue-specific patterns.
Figure 6: Fat and skin Treg cells are polarized like TH2 cells.
Figure 7: Identification of tisTregST2 cells.
Figure 8: Characterization of the tisTregST2 cell population.

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Acknowledgements

We thank A. Rudensky (Memorial Sloan-Kettering Cancer Center) for mice; F. Lyko for help with amplicon sequencing; Z. Gu for bioinformatics support; S. Schmitt, M. Wühl and F. Ilmberger for laboratory support; and the DKFZ core facilities Preclinical Research, Flow Cytometry and Genomics & Proteomics for technical support. Supported by the Helmholtz Association of German Research Centers (HZ-NG-505 to M.F.), the European Research Council (ERC-2015-CoG, #648145 REGiREG to M.F.), the German-Israeli Helmholtz Research School in Cancer Biology (M.D.) and the German Ministry of Research and Education (031L0076A and 01KU1216B to B.B.).

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M.D., C.D.I., A.B., A.H.-W., Q.W., F.F., C.H., B.B. and M.F. analyzed data; M.D., D.W., C.P. and M.F. designed the study; M.D., D.W., P.A.L. and M.F. designed experiments; M.D., D.W., U.T., A.-C.H., D.K., J.-P.M. and K.B. performed the experiments; and M.D. and M.F. wrote the manuscript.

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Correspondence to Markus Feuerer.

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Delacher, M., Imbusch, C., Weichenhan, D. et al. Genome-wide DNA-methylation landscape defines specialization of regulatory T cells in tissues. Nat Immunol 18, 1160–1172 (2017). https://doi.org/10.1038/ni.3799

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