DNA Methylation in Regulatory T Cell Differentiation and Function: Challenges and Opportunities

As a bona fide epigenetic marker, DNA methylation has been linked to the differentiation and function of regulatory T (Treg) cells, a subset of CD4 T cells that play an essential role in maintaining immune homeostasis and suppressing autoimmunity and antitumor immune response. DNA methylation undergoes dynamic regulation involving maintenance of preexisting patterns, passive and active demethylation, and de novo methylation. Scattered evidence suggests that these processes control different stages of Treg cell lifespan ranging from lineage induction to cell fate maintenance, suppression of effector T cells and innate immune cells, and transdifferentiation. Despite significant progress, it remains to be fully explored how differential DNA methylation regulates Treg cell fate and immunological function. Here, we review recent progress and discuss the questions and challenges for further understanding the immunological roles and mechanisms of dynamic DNA methylation in controlling Treg cell differentiation and function. We also explore the opportunities that these processes offer to manipulate Treg cell suppressive function for therapeutic purposes by targeting DNA methylation.