Transcriptional regulation and development of regulatory T cells

Abstract

Regulatory T (Treg) cells are a distinct subset of CD4⁺ T cells. Instead of triggering adaptive immunity, they suppress immune responses. Small numbers of Treg cells reside within lymphoid organs and peripheral tissues, but their contribution to immune tolerance is so significant that defects in Treg cell function cause catastrophic immune disorders. Since they were first discovered 20 years ago, efforts have been made to understand the differences in developmental processes between Treg cells and conventional T cells that determine the ultimate fate of the overall T-cell population. Transcription factor Foxp3 is crucial for Treg cell differentiation, but it is not the whole story. Owing to recent advances in Treg cell research, we are now on the verge of appreciating the comprehensive mechanisms underlying Treg cell generation. Here, we discuss major discoveries, active study topics and remaining questions regarding Treg cell development.

Figure 1

Schematic diagram of transcriptional regulation of the Foxp3 locus. Regulatory regions of the Foxp3 locus including the promoter CNS1, CNS2, CNS3, and recently discovered CNS0 are shown. Transcription factors (TFs) binding to each regulatory region and the function of each regulatory region are shown.

Figure 2

Schematic diagram of Treg cell development. tTreg cells develop in the thymus by two-step process. First, high-affinity tissue-restricted self-antigens presented by medullary thymic epithelial cells (mTECs) or bone-marrow derived antigen-presenting cells (BM-APCs) derive single-positive (SP) T cells into Treg pathway. Second, cytokine IL-2 or IL-15 derives the precursor cells into fully committed tTreg cells. pTreg cells develop in the periphery by environmental antigens such as microbial antigens or food antigens presented by mucosal tissue-resident dendritic cells (DCs). TGF-β, retinoic acids (RAs) and short chain fatty acids (SCFAs) produced in the immunosuppressive environments promote pTreg development.