The role of transcription factors in shaping regulatory T cell identity

Forkhead box protein 3-expressing (FOXP3⁺) regulatory T cells (T_reg cells) suppress conventional T cells and are essential for immunological tolerance. FOXP3, the master transcription factor of T_reg cells, controls the expression of multiples genes to guide T_reg cell differentiation and function. However, only a small fraction (<10%) of T_reg cell-associated genes are directly bound by FOXP3, and FOXP3 alone is insufficient to fully specify the T_reg cell programme, indicating a role for other accessory transcription factors operating upstream, downstream and/or concurrently with FOXP3 to direct T_reg cell specification and specialized functions. Indeed, the heterogeneity of T_reg cells can be at least partially attributed to differential expression of transcription factors that fine-tune their trafficking, survival and functional properties, some of which are niche-specific. In this Review, we discuss the emerging roles of accessory transcription factors in controlling T_reg cell identity. We specifically focus on members of the basic helix-loop-helix family (AHR), basic leucine zipper family (BACH2, NFIL3 and BATF), CUT homeobox family (SATB1), zinc-finger domain family (BLIMP1, Ikaros and BCL-11B) and interferon regulatory factor family (IRF4), as well as lineage-defining transcription factors (T-bet, GATA3, RORγt and BCL-6). Understanding the imprinting of T_reg cell identity and specialized function will be key to unravelling basic mechanisms of autoimmunity and identifying novel targets for drug development.