Development and Functional Modulation of Regulatory T Cells by Transcription Factors and Epigenetics.

Regulatory T cells (Tregs) are essential for the maintenance of immune homeostasis. Studies of Treg are not only necessary for understanding the mechanism of immune homeostasis but also extremely useful for the development of treatments of various immune diseases. Forkhead box P3 (Foxp3) was identified as the master gene responsible for the immune-suppressing activity of Tregs. The promoter region and several intronic enhancers, designated conserved noncoding sequence (CNS) 0, 1, 2, and 3, at the Foxp3 gene locus have important roles in Foxp3 expression and Treg development. We demonstrated that transcription factors Nr4a and Smad2/3 are required for development of thymic Tregs and induced Tregs, respectively. In addition to transcription factors, Treg-specific DNA demethylation has been shown to be important for Treg stability. In particular, DNA demethylation of CNS2 was implicated in Treg stability, and members of the ten-eleven translocation family of demethylation factors were recently demonstrated to have important roles in 5'-C-phosphate-G-3' demethylation at CNS2. This article summarizes recent findings regarding the roles of transcription factors and epigenetic modifications in the differentiation, maintenance, and function of Tregs. This review will facilitate clinical application of Tregs to diseases in the field of ophthalmology, including uveitis and age-related macular degeneration.