Regulation of Regulatory T Cells: Epigenetics and Plasticity

doi:10.1016/B978-0-12-800147-9.00008-X

Advances in Immunology

Volume 124, 2014, Pages 249-273

https://doi.org/10.1016/B978-0-12-800147-9.00008-X Get rights and content

Abstract

Regulatory T (Treg) cells, as central mediators of immune suppression, play crucial roles in many aspects of immune system's physiology and pathophysiology. The transcription factor Foxp3 has been characterized as a master gene of Tregs. Yet Treg cells possess a distinct pattern of gene expression, including upregulation of immune-suppressive genes and silencing of inflammatory cytokine genes. Recent studies have revealed the molecular mechanisms that establish and maintain such gene regulation in Treg cells. This review discusses recent progress in our understanding of molecular features of Treg cells, with particular attention to Treg-cell lineage commitment and stability.

Introduction

A variety of autoimmune and allergic disease pathologies are caused by immune responses to “self” antigens, environmental nonmicrobial antigens, and infectious agents. Regulatory T (Treg) cells, which play an indispensable role in immunological tolerance, protecting the host from excessive immune responses, are characterized by expression of the Forkhead transcription factor Foxp3. Foxp3 plays an essential role in the suppressive function of Tregs, and Foxp3 deficiency causes a multiorgan autoimmune disease, which can be observed in the scurfy mouse and in patients with immunodysregulation polyendocrinopathy enteropathy X-linked syndrome (Sakaguchi et al., 2008, Wan and Flavell, 2007). Foxp3 is induced in naturally occurring Tregs (called nTregs or more recently thymic Tregs [tTregs]) during their development in the thymus under the influence of relatively high-avidity interactions of T-cell receptors (TCRs) with self-antigens (Lee, Bautista, & Hsieh, 2011). Foxp3⁺ Tregs can also be generated from naïve T cells by TCR stimulation in the presence of TGF-β and IL-2; the resulting cells are called induced Tregs (iTregs or peripheral Tregs [pTregs]). Although iTregs exert an in vitro suppression activity similar to that of nTregs, the Foxp3 expression of iTregs was shown to be unstable in vivo (Chen et al., 2011, Floess et al., 2007, Koenecke et al., 2009). Various transcription factors including c-Rel, Smad2/3, and Runx1 have been identified as important for nTreg and iTreg induction through their transactivation of the Foxp3 promoter and/or enhancers (Ohkura et al., 2011, Takimoto et al., 2010). In addition, we have recently shown that the Nr4a family of transcription factors, which could be direct sensors of TCR strength, are essential for nTreg development in the thymus (Sekiya et al., 2013).

Although the Treg suppression mechanism is now well characterized (Wing & Sakaguchi, 2012), the molecular mechanisms of Treg development and maintenance remain to be clarified. nTregs have been shown to convert to certain types of effector helper T cells such as Th1, Th17, and follicular helper T (Tfh) cells after losing Foxp3 expression (Komatsu et al., 2009, Tsuji et al., 2009). These ex-Foxp3 cells, so-called as they are derived from Foxp3⁺ Treg cells but have lost their Foxp3 expression, develop an effector-memory phenotype, produce pathogenic cytokines, and may be involved in triggering the development of autoimmunity. In contrast, a recent study by Miyao et al. (2012) clearly denied Treg reprogramming. Nevertheless, it remains an open question how the expression and stability of Foxp3 in Tregs are regulated.

Section snippets

Generation of nTregs in the Thymus

nTregs develop from progenitor CD4⁺CD8⁺ double-positive (DP) T cells as do other single-positive (SP) T cells (Fig. 8.1). As a result of TCR gene rearrangement, T cells that possess TCR but fail to receive the appropriate TCR signal go into “death by neglect,” which is also called “positive selection.” In contrast, high-affinity ligands, mostly from self-proteins presented on MHC molecules on thymic antigen-presenting cells, trigger clonal deletion by direct induction of apoptosis. This process

Factors Involved in Foxp3 Expression

The next question concerns how strong TCR signals induce Foxp3 expression. The Foxp3 promoter has been extensively studied: Mantel et al. (2006) first characterized the human Foxp3 promoter, which is located 6.5 kb upstream of the first exon, and found six NFAT and AP-1 binding sites and a TATA and CAAT box (Mantel et al., 2006). The promoter is highly conserved between humans, mice, and rats; in addition, three highly conserved noncoding DNA sequences (CNS), CNS1, CNS2, and CNS3, were

Generation of Tregs by TGF-β

The role of TGF-β in nTreg differentiation is still controversial. Mice deficient in CNS1 exhibit alterations in iTreg but not nTreg differentiation (Zheng et al., 2010). Selective impairment of iTreg differentiation due to CNS1 deletion results in spontaneous allergic Th2-type inflammation in the intestine and lungs under a B6 background (Josefowicz et al., 2012). T-cell-specific deletion of the TGF-β receptor II or Smad2 and Smad3 cause very severe fatal inflammation, but thymic nTreg

Differences Between nTregs and iTregs

Several groups have used microarray analyses to unveil the developmental and functional differences between nTreg and iTreg cells (Feuerer et al., 2010, Hill et al., 2007). iTreg and nTreg cells were shown to be genetically distinct. Among the genes differentially expressed, Ikzf2 (Helios) and Nrp1 (Neuropilin-1) expressions have often been used as markers of nTreg cells compared with iTreg cells. Semaphorin-4a (Sema4a) and the Treg-cell-expressed receptor Nrp1 interact with each other. Sema4a

Epigenetic Changes in Tregs and Their Role in Treg Stability

Unlike nTregs, iTregs have been shown to be unstable. This is a significant obstacle to the use of ex vivo-expanded iTregs for adoptive immune therapy (Koenecke et al., 2009). This unstable phenotype is associated with a strong methylation of the CNS2 region of the TSDRs within the Foxp3 locus. This idea is supported by the fact that treatment of iTregs with IL-2/anti-IL-2 complexes in the presence of an antigen stabilized Foxp3 expression while also enhancing demethylation of the TSDR (Chen et

Treg Stability and Its Implication in Immunological Diseases

The continuous presence of Tregs throughout life is necessary to avoid autoimmunity (Kim, Rasmussen, & Rudensky, 2007). Thus, the stability of Foxp3 expression influences the balance between tolerance and autoimmunity, and loss of Foxp3 in Tregs may underlie the pathogenesis of autoimmune diseases and infection (Komatsu et al., 2014, Oldenhove et al., 2009, Yang et al., 2008, Zhou et al., 2009). nTregs have been shown to convert to certain types of effector helper T cells such as Th1, Th17, and

Factors that Control Treg Stability

Most reports have suggested, however, that these unstable Foxp3⁺ cell subsets constitute a minor fraction under ordinary conditions and only increase under lymphopenic or inflammatory conditions. Moreover, Foxp3 has been shown to be stable in bona fide Tregs (Miyao et al., 2012, Rubtsov et al., 2010). Thus, there must be a mechanism(s) that prevents the pathogenic conversion of nTregs. As mentioned before, hypomethylation of TSDR is a key factor in the stability of Tregs. In addition, several

Conclusion

As shown here, Treg-cells possess the potential to treat a wide range of immunological diseases from autoimmune conditions to allergies to cancer. For the treatment of autoimmune disorders and allergies, and to promote the efficient acceptance of grafts after transplantation, the adoptive transfer of Treg cells that have been expanded ex vivo or induced in vitro is attempted. The ultimate goal of this approach is to control inflammation with minimum adverse effects through the administration of

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The transcriptional regulation of Foxp3 expression and Treg differentiation is summarized in Fig. -1. The Foxp3 gene contains a promoter region and three conserved non-coding sequences (CNS1, 2 & 3) in human, mouse and rat [26,27]. More recently, Kitagawa et al. reported CNS0, another conserved region bound by Satb1, which is a chromatin organizer that can activate super-enhancers even in closed chromatin where chromatin accessibility is low [28].
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^☆: Competing Interests: The authors have declared that no competing interests exist.

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Chapter Eight - Regulation of Regulatory T Cells: Epigenetics and Plasticity☆

Abstract

Introduction

Section snippets

Generation of nTregs in the Thymus

Factors Involved in Foxp3 Expression

Generation of Tregs by TGF-β

Differences Between nTregs and iTregs

Epigenetic Changes in Tregs and Their Role in Treg Stability

Treg Stability and Its Implication in Immunological Diseases

Factors that Control Treg Stability

Conclusion

Immunity

Immunity

Immunity

Immunity

Immunity

Immunity

Immunity

Immunity

Advances in Immunology

Immunity

Cell

Immunity

Trends in Immunology

Immunity

Immunity

Mucosal Immunology

Immunity

Trends in Pharmacological Sciences

Immunity

Immunity

Immunity

Cell

Immunity

The Journal of Biological Chemistry

Immunity

Immunity

Immunity

Blood

Activation-induced FOXP3 in human T effector cells does not suppress proliferation or cytokine production

International Immunology

Metabolites produced by commensal bacteria promote peripheral regulatory T-cell generation

Nature

Treg induction by a rationally selected mixture of Clostridia strains from the human microbiota

Nature

Induction of colonic regulatory T cells by indigenous Clostridium species

Science

Regulation of T-cell tolerance by calcium/NFAT signaling

Immunological Reviews

NFATc2 and NFATc3 transcription factors play a crucial role in suppression of CD4 + T lymphocytes by CD4 + CD25 + regulatory T cells

The Journal of Experimental Medicine

IL-2 receptor beta-dependent STAT5 activation is required for the development of Foxp3 + regulatory T cells

Journal of Immunology

A role for the orphan steroid receptor Nur77 in apoptosis accompanying antigen-induced negative selection

Immunity

Deficiency of the Src homology region 2 domain-containing phosphatase 1 (SHP-1) causes enrichment of CD4+CD25 + regulatory T cells

Journal of Immunology

IL-2 controls the stability of Foxp3 expression in TGF-beta-induced Foxp3 + T cells in vivo

Journal of Immunology

A functionally specialized population of mucosal CD103 + DCs induces Foxp3 + regulatory T cells via a TGF-beta and retinoic acid-dependent mechanism

The Journal of Experimental Medicine

c-Rel but not NF-kappaB1 is important for T regulatory cell development

European Journal of Immunology

Stability and function of regulatory T cells is maintained by a neuropilin-1-semaphorin-4a axis

Nature

Identification of T helper type 1-like, Foxp3 + regulatory T cells in human autoimmune disease

Nature Medicine

Nuclear receptor Nr4a1 modulates both regulatory T-cell (Treg) differentiation and clonal deletion

Proceedings of the National Academy of Sciences of the United States of America

Genomic definition of multiple ex vivo regulatory T cell subphenotypes

Proceedings of the National Academy of Sciences of the United States of America

Epigenetic control of the foxp3 locus in regulatory T cells

PLoS Biology

A multiply redundant genetic switch ‘locks in’ the transcriptional signature of regulatory T cells

Nature Immunology

Commensal microbe-derived butyrate induces the differentiation of colonic regulatory T cells

Nature

Requirements of transcription factor Smad-dependent and -independent TGF-beta signaling to control discrete T-cell functions

Proceedings of the National Academy of Sciences of the United States of America