Vitamin C and DNA demethylation in regulatory T cells

Abstract

For the immune homeostasis, regulation of effector T cells is indispensable. This is performed by a distinct subclass of CD4+ T cell called "regulatory T cells" (Tregs). The Tregs express the canonical transcription factor called Forkhead box P3 (Foxp3) throughout their life span for their proper development and suppressive function, and the expression of Foxp3 is regarded as a reliable marker of Tregs. Tregs can be generated in the thymus, peripheral tissues, and even in vitro. Thus, Treg populations are divided into three groups. The first one is the Tregs generated in the thymus (thymic Treg, tTreg) and occupies the major fraction of the total Treg population in vivo. The second one is the minor fraction generated in periphery from naive CD4+ T cells, when they meet cognate antigen under tolerogenic conditions (peripheral Treg, pTreg). Tregs can also be generated in vitro upon TCR activation in the presence of TGF-β (induced Treg, iTreg). Although all three Treg populations have suppressive activity in common, each population shows distinct genetic and epigenetic features. For instance, in Foxp3 gene there is a unique evolutionarily conserved intronic region with several CpG motifs, which is called CNS2 (conserved non-coding sequence 2). The CpG motifs in CNS2 are fully methylated in almost all Foxp3 T cells including CD4 single positive thymocytes (tTreg precursors), naive CD4+ T cells (pTreg and iTreg precursors) and CD8+ T cells, and some Foxp3+ T cells such as iTregs. In contrast, they are fully demethylated in Tregs generated in vivo (tTregs and pTregs). This dichotomic pattern seen in CNS2 (de-)methylation has attracted researchers' attention. In this chapter, we are going to discuss the underlying mechanisms of CNS2 demethylation in various types of Tregs and how vitamin C contributes to this process.