Regulatory T cell identity: formation and maintenance

•Foxp3 CNS2 is a gatekeeper between regulatory and conventional T cell lineages.•TCR and IL-2 signals dictate both differentiation and stability of Treg cells.•Dynamic enhancer:promoter interaction is required for stable Foxp3 expression.

T regulatory (Treg) cells are central to the maintenance of immune homeostasis. The transcription factor forkhead box P3 (Foxp3) is essential for specifying the Treg cell lineage during development, and continued expression of Foxp3 in mature Treg cells is necessary for suppressive function. Loss of Foxp3 expression in Treg cells is associated with autoimmune pathology. Here, we review recent insights into the mechanisms that maintain Treg cell stability and function, and place these findings within the broader understanding of mechanisms that establish Treg cell identity during development. We integrate emerging principles in Treg cell lineage maintenance with the mechanisms that allow Treg cells to sense and respond to varied inflammatory environments, and outline important areas of future inquiry in this context.