The role of transcription factors in shaping regulatory T cell identity

Abstract

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.

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.

Figure 2.. The coordinated network of accessory and lineage-specifying transcription factors regulating FOXP3 expression.

Engagement of T cell receptors (TCRs) by antigen-presenting cells (APCs) through the MHC class II-antigen complex, signalling of interleukin-2 (IL-2) via the CD25-STAT5 module, and activation of canonical transforming growth factor-β (TGFβ)-dependent SMAD pathways all work together to promote the differentiation of regulatory T cells (T_reg cells) and expression of forkhead box protein 3 (FOXP3). Other signals, such as cytokines and endogenous chemical compounds present in the environment, are detected by specific cell-surface receptors and transcription factors, such as AHR and RORγt. These signals are integrated along with additional transcriptional regulators (such as BACH2, MAF, Ikaros, Aiolos, RUNX1, FOXO1, SATB1 and NFIL3) at conserved noncoding sequence (CNS) regions of FOXP3. Together, these regulate expression of FOXP3 and the intracellular mechanisms required to activate T_reg cell suppressive functions through cell contact or soluble factors. These transcriptional regulators also form stimulatory and inhibitory complexes that regulate genes involved in the maintenance of hallmark and specialized genes expressed by T_reg cells, as summarized in Table 2.