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

Regulatory T cells (T(reg)) perform two distinct functions: they maintain self-tolerance and support organ homeostasis by differentiation into specialized tissue T(reg) cells. We now report that epigenetic modifications define molecular characteristics of tissue T(reg) cells. Tagmentation-based whole-genome bisulfite sequencing of tissue and lymphoid T cells revealed more than 11,000 differentially methylated regions. Similarities of the epigenetic landscape led to the identification of a common tissue T(reg) population, present in many organs and characterized by gain and loss of DNA methylation, including many T(H)2-associated sites such as the IL-33 receptor ST2, and the production of tissue-regenerative factors. Furthermore, this ST2-expressing population (which we term here tisT(reg)ST2) was dependent on the transcriptional regulator BATF and could be expanded by IL-33. Thus, tissue T(reg) cells integrate different waves of epigenetic reprogramming which define their tissue-restricted specializations.