It takes two

Expression of the transcription factor Foxp3 is essential but might not be sufficient for the development of regulatory T cells (T_reg cells). In Immunity, Sakaguchi and colleagues show that hypomethylation of certain T_reg cell–representative gene regions is required for the development of natural T_reg cells (nT_reg cells) and that it is established in the thymus independently of Foxp3 expression. CpG hypomethylation of limited regions (Foxp3 intron 1, Tnfrsf18 exon 5, Ctla4 exon 2 and Ikzf4 intron 1b) is exclusively 'imprinted' in nT_reg cells and not in other T cell populations, including inducible T_reg cells. Hypomethylation of the nT_reg cell type is required for Foxp3⁺ T cells to acquire nT_reg cell–type gene expression and full suppressive activity and to sustain the expression of T_reg cell–associated molecules such as Foxp3, CLTA-4 and CD25. The induction of such hypomethylation in developing nT_reg cells is dependent on engagement of the TCR by self ligands in the thymus.

Immunity 37, 785–799 (2012)