DNA hypomethylation traits define human regulatory T cells in cutaneous tissue and identify their blood recirculating counterparts.

CD4(+) regulatory T (T(reg)) cells in tissues play crucial immunoregulatory and regenerative roles. Despite their importance, the epigenetics and differentiation of human tissue T(reg) cells are incompletely understood. Here, we performed genome-wide DNA methylation analysis of human T(reg) cells from skin and blood and integrated these data into a multiomic framework, including chromatin accessibility and gene expression. This analysis identified programs that governed the tissue adaptation of skin T(reg) cells. We found that subfamilies of transposable elements represented a major constituent of the hypomethylated landscape in tissue T(reg) cells. Based on T cell antigen receptor sequence and DNA hypomethylation homologies, our data indicate that blood CCR8(+) T(reg) cells contain recirculating human skin T(reg) cells. Conversely, differences in chromatin accessibility and gene expression suggest a certain reversal of the tissue adaptation program during recirculation. Our findings provide insights into the biology of human tissue T(reg) cells, which may help harness these cells for therapeutic purposes.