Genetic and epigenetic basis of Treg cell development and function: from a FoxP3‐centered view to an epigenome‐defined view of natural Treg cells

<jats:title>Summary</jats:title><jats:p>Naturally occurring regulatory T (nTreg) cells, which specifically express the transcription factor Forkhead box protein P3 (FoxP3), are indispensable for the maintenance of immunological self‐tolerance and homeostasis. Recent studies have shown that developing nTreg cells in the thymus acquire a Treg‐specific and stable hypomethylation pattern in a limited number of genes, which encode key molecules including FoxP3, essential for Treg cell function. This epigenetic change is acquired via T‐cell receptor (<jats:styled-content style="fixed-case">TCR</jats:styled-content>) stimulation, beginning prior to FoxP3 expression. The Treg‐specific <jats:styled-content style="fixed-case">DNA</jats:styled-content> hypomethylated regions generally act as gene enhancers in steady state nTreg cells, contributing to the stable expression of Treg function‐associated key genes including <jats:italic>Ctla4</jats:italic>,<jats:italic> Il2ra</jats:italic>, and <jats:italic>Ikzf4</jats:italic> in addition to <jats:italic>Foxp3</jats:italic>. Upon <jats:styled-content style="fixed-case">TCR</jats:styled-content> stimulation of mature nTreg cells, FoxP3 strongly represses many genes including <jats:italic>Il2</jats:italic>, contributing to Treg suppressive activity. Thus, the Treg‐specific epigenome alteration can determine the heritable Treg‐specific gene network including <jats:italic>Foxp3</jats:italic> regulation. Considering physiological presence of non‐suppressive FoxP3<jats:sup>+</jats:sup> T cells in the immune system and loss of FoxP3 in Treg cells under certain immunological conditions, functional nTreg cells can be more accurately defined as a T‐cell subpopulation possessing the Treg‐type epigenome, rather than FoxP3<jats:sup>+</jats:sup> T cells. This epigenome‐based definition of Treg cells would enable better understanding of functional stability, plasticity, and heterogeneity of Treg cells.</jats:p>