Figure 1. Accessory transcription factors in regulatory T cell specification and maturation.

Thymocytes or naive CD4⁺ T cells differentiate into regulatory T (T_reg) cells following T cell receptor (TCR) engagement within microenvironments rich in T_reg cell-inducing soluble factors, such as interleukin-2 (IL-2) and transforming growth factor-β (TGFβ). The coordinated integration of multiple accessory transcription factors (TFs) drive T_reg cell specification and epigenetic changes (such as at the T_reg cell-specific demethylated region (TSDR)) that are indispensable for stable expression of forkhead box protein 3 (FOXP3). T_reg cell maturation to effector T_reg cells is driven by FOXP3-dependent and FOXP3-independent accessory TFs that induce FOXP3 expression and enhance production of effector (suppressive) cytokines. Some TFs, such as NFIL3, have the ability to repress FOXP3 expression. Mature effector T_reg cells can also be induced to express additional accessory programmes driven by TFs usually associated with lineage-specification in conventional T cells. These shape the unique features of specialized subpopulations of T_reg cells, such as tissue homing.