Control of regulatory T‐cell differentiation and function by T‐cell receptor signalling and Foxp3 transcription factor complexes

The transcription factor Foxp3 controls the differentiation and function of regulatory T-cells (Treg). Studies in the past decades identified numerous Foxp3-interacting protein partners. However, it is still not clear how Foxp3 produces the Treg-type transcriptomic landscape through cooperating with its partners. Here I show the current understanding of how Foxp3 transcription factor complexes regulate the differentiation, maintenance and functional maturation of Treg. Importantly, T-cell receptor (TCR) signalling plays central roles in Treg differentiation and Foxp3-mediated gene regulation. Differentiating Treg will have recognized their cognate antigens and received TCR signals before initiating Foxp3 transcription, which is triggered by TCR-induced transcription factors including NFAT, AP-1 and NF-κB. Once expressed, Foxp3 seizes TCR signal-induced transcriptional and epigenetic mechanisms through interacting with AML1/Runx1 and NFAT. Thus, Foxp3 modifies gene expression dynamics of TCR-induced genes, which constitute cardinal mechanisms for Treg-mediated immune suppression. Next, I discuss the following key topics, proposing new mechanistic models for Foxp3-mediated gene regulation: (i) how Foxp3 transcription is induced and maintained by the Foxp3-inducing enhanceosome and the Foxp3 autoregulatory transcription factor complex; (ii) molecular mechanisms for effector Treg differentiation (i.e. Treg maturation); (iii) how Foxp3 activates or represses its target genes through recruiting coactivators and corepressors; (iv) the 'decision-making' Foxp3-containing transcription factor complex for Th17 and Treg differentiation; and (v) the roles of post-translational modification in Foxp3 regulation. Thus, this article provides cutting-edge understanding of molecular biology of Foxp3 and Treg, integrating findings by biochemical and genomic studies.