Transcriptional and epigenetic basis of Treg cell development and function: its genetic anomalies or variations in autoimmune diseases

Naganari Ohkura,Shimon Sakaguchi

doi:10.1038/s41422-020-0324-7

Abstract

Naturally arising regulatory CD4+ T (Treg) cells, which specifically express the transcription factor FoxP3 in the nucleus and CD25 and CTLA-4 on the cell surface, are a T-cell subpopulation specialized for immune suppression, playing a key role in maintaining immunological self-tolerance and homeostasis. FoxP3 is required for Treg function, especially for its suppressive activity. However, FoxP3 expression per se is not necessary for Treg cell lineage commitment in the thymus and insufficient for full Treg-type gene expression in mature Treg cells. It is Treg-specific epigenetic changes such as CpG demethylation and histone modification that can confer a stable and heritable pattern of Treg type gene expression on developing Treg cells in a FoxP3-independent manner. Anomalies in the formation of Treg-specific epigenome, in particular, Treg-specific super-enhancers, which largely include Treg-specific DNA demethylated regions, are indeed able to cause autoimmune diseases in rodents. Furthermore, in humans, single nucleotide polymorphisms in Treg-specific DNA demethylated regions associated with Treg signature genes, such as IL2RA (CD25) and CTLA4, can affect the development and function of naïve Treg cells rather than effector T cells. Such genetic variations are therefore causative of polygenic common autoimmune diseases including type 1 diabetes and rheumatoid arthritis via affecting endogenous natural Treg cells. These findings on the transcription factor network with FoxP3 at a key position as well as Treg-specific epigenetic landscape facilitate our understanding of Treg cell development and function, and can be exploited to prepare functionally stable FoxP3-expressing Treg cells from antigen-specific conventional T cells to treat autoimmune diseases.

Highlights

1234567890();,: INTRODUCTION Naturally occurring Treg cells, which constitute ~10% of CD4+ T cells in healthy individuals, constitutively express the transcription factor FoxP3 in the nucleus, CD25 and CTLA-4 on the cell surface as Treg functionassociated molecules
These results collectively suggest that Treg-specific DNA hypomethylation is developmentally generated in the genome of Naturally occurringTreg (nTreg) cells and heritable along their proliferation in the periphery, and that Treg-specific DNA demethylated regions (Treg-DRs) act as specific enhancers for up-regulation of Treg signature gene expression largely in a FoxP3-independent manner
The results indicate that autoimmune single nucleotide polymorphisms (SNPs) mapped to the genes associated with T-cell functions are predominantly associated with loss-of-function in Treg cells, rather than gain-offunction in effector Tconv cells, thereby rendering the host susceptible to common autoimmune diseases

Summary

REVIEW ARTICLE

Transcriptional and epigenetic basis of Treg cell development and function: its genetic anomalies or variations in autoimmune diseases. In humans, single nucleotide polymorphisms in Treg-specific DNA demethylated regions associated with Treg signature genes, such as IL2RA (CD25) and CTLA4, can affect the development and function of naïve Treg cells rather than effector T cells Such genetic variations are causative of polygenic common autoimmune diseases including type 1 diabetes and rheumatoid arthritis via affecting endogenous natural Treg cells. It is of note that the expression levels of these Treg function-associated molecules are slightly lower in FoxP3-deficient Treg cells compared with FoxP3-intact ones, suggesting a certain contribution of FoxP3 to up-regulation of the transcription of these genes, as further discussed below These results collectively suggest that Treg-specific DNA hypomethylation is developmentally generated in the genome of nTreg cells and heritable along their proliferation in the periphery, and that Treg-specific DNA demethylated regions (Treg-DRs) act as specific enhancers for up-regulation of Treg signature gene expression largely in a FoxP3-independent manner. FoxP3 is able to actively repress gene transcription of key modulators of T cell activation and function by recruiting the HAT/HDAC

Review Article

472 CONCLUSIONS AND PERSPECTIVE