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

Regulatory T cells (T_reg cells) perform two distinct functions: they maintain self-tolerance, and they support organ homeostasis by differentiating into specialized tissue T_reg cells. We found that epigenetic modifications defined the molecular characteristics of tissue T_reg cells. Tagmentation-based whole-genome bisulfite sequencing revealed more than 11,000 regions that were methylated differentially in pairwise comparisons of tissue T_reg cell populations and lymphoid T cells. Similarities in the epigenetic landscape led to the identification of a common tissue T_reg 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 T_H2 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 T_reg cells integrate multiple waves of epigenetic reprogramming that define their tissue-restricted specialization.