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Epigenetic Variability of CD4+CD25+ Tregs Contributes to the Pathogenesis of Autoimmune Diseases

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Epigenetic Variability of CD4+CD25+ Tregs Contributes to the Pathogenesis of Autoimmune Diseases Clinic Rev Allerg Immunol DOI 10.1007/s12016-016-8590-3 Epigenetic Variability of CD4+CD25+ Tregs Contributes to the Pathogenesis of Autoimmune Diseases Ye Shu1,2 & Qinghua Hu3 & Hai Long1 & Christopher Chang4 & Qianjin Lu1 & Rong Xiao1 # Springer Science+Business Media New York 2016 Abstract Autoimmune diseases are characterized by aberrant andtrimethylationlevelsofhistoneH3andH4whencompared immune responses against healthy cells and tissues. However, with effector T cells, leading to an open chromatin structure. the exact mechanisms underlying the development of these MicroRNAs such as miR-155, miR-126, and miR-10a also conditions remain unknown. CD4+CD25+ regulatory T cells exert an important influence on the differentiation, develop- (Tregs) are a subset of mature T cells which have an important ment, and immunological functions of Tregs. Aberrant epige- role in maintaining immune homeostasis and preventing au- netic modifications affecting Foxp3 and other key genes in toimmune diseases. Forkhead box p3 (Foxp3), a member of Tregs contribute to disease activity and tissue inflammation in the fork head transcription factor family, is recognized as a autoimmune diseases, which holds great potential for providing marker of CD4+CD25+ Tregs. The decreased number and/ novel targets for epigenetic therapies. Advances in research into or function of CD4+CD25+ Tregs in peripheral blood and the epigenetic regulation of CD4+CD25+ Tregs may also lead related tissues has been demonstrated in systemic lupus to the identification of new epigenetic biomarkers for diagnosis erythematosus, systemic sclerosis, and other autoimmune and prognosis. diseases, which are at least partially regulated by epigenetic mechanisms. Epigenetics refers to the study of potentially Keywords Tregs . Foxp3 . Epigenetic mechanism . heritable alterations in gene expression without underlying Autoimmune diseases . DNA methylation . Histone changes of the nucleotide sequence, mainly including DNA deacetylation . MicroRNA methylation, histone modification, and microRNAs (miRNAs). For example, DNA methylation status of CpG islands on the Foxp3 gene, which may be affected by normal aging and regulated by environmental factors, plays an impor- Abbreviations tant role in modulating the homeostasis of Foxp3 expression 5-Aza-2′- 5-Aza-2′-deoxycytidine in Tregs. Foxp3 gene in Tregs also shows distinct acetylation dC ATF Activating transcription factor ATRA All-trans retinoic acid * Rong Xiao [email protected] CNS Conserved noncoding DNA sequence CREB cAMP response element binding protein 1 Department of Dermatology, The Second Xiangya Hospital, Central CTLA-4 Cytotoxic T lymphocyte-associated antigen-4 South University, Hunan Key Laboratory of Medical Epigenetics, CXCR4 Chemokine receptor 4 Changsha, China DEP Diesel exhaust particles 2 Department of Dermatology, Hunan Province Children’sHospital, DMR Differentially methylated region Changsha, China Foxp3 Forkhead box p3 3 Department of Cardiovascular Surgery, Xiangya Hospital, Central HDACi Histone deacetylase inhibitor South University, Changsha, China IL-2 Interleukin-2 4 Division of Rheumatology, Allergy and Clinical Immunology, KLF Kruppel-like factor University of California at Davis, Davis, CA, USA MSP Methylation-specific PCR Clinic Rev Allerg Immunol NFAT Nuclear factor of activated T cells Forkhead box p3 (Foxp3) is a member of the fork head NF-kB Nuclear factor-kB transcription factor family and is exclusively expressed in PAH Polycyclic aromatic hydrocarbons CD4+CD25+ Treg cells [1]. Foxp3 plays an important role PD-1 Programmed death-1 in the growth, differentiation, and function of Tregs and is SLE Systemic lupus erythematosus recognized as a marker of CD4+CD25+ Treg cells. In 2001, SOCS1 Suppressorofcytokinesignaling1 Brunkow et al. [2] were the first to report Foxp3 in a study on STAT5 Signal transducer and activator of transcription 5 the Scurfy mouse. Because of a mutation in the Foxp3 gene, TGF-β Transforming growth factor-β the Scurfy mice suffered from CD4+ T cell-mediated lympho- TGP Total glucosides of paeony cyte proliferative diseases and showed cachexia and lympho- TNFR Tumor necrosis factor receptor cyte infiltration in multiple organs. Interestingly, the Scurfy TRAIL- Tumor necrosis factor-related apoptosis-induc- mice recovered from the lymphoproliferative disorders after DR5 ing ligand-death receptor 5 adoptive transfer of normal CD4+CD25+ Tregs. Furthermore, Tregs CD4+CD25+ regulatory T cells FOXP3 transgenic mice had an increased number of CD4+ TSA Trichostatin A CD25+ Tregs, whereas FOXP3 knockout mice lacked CD4+ TSDR Treg-specific demethylated region CD25+ Tregs.Wildin et al. [3] and Bennett et al. [4] found that human and murine Foxp3 genes are homologous and that mutations in FOXP3 caused human IPEX syndrome, which is characterized by immune dysfunction, multiple endocrine Introduction diseases, intestinal disease, and X chromosome linkage syndrome. Patients with an autoimmune disease have an abnormal acti- vation of immunocompetent cells, which is associated with Signaling Pathways Inducing the Expression the production of large amounts of autoantibodies and damage of CD4+CD25+ Tregs to multiple organs. However, the exact pathogenesis of auto- immune disease remains unclear. CD4+CD25+ regulatory T The TCR signaling pathway plays a key role in the differen- cells (Tregs) are a subset of mature T cells which has an im- tiation of CD4+CD25+ Tregs [5]. Numerous transcription fac- portant role in maintaining immune homeostasis and tors in the downstream TCR signaling pathway, such as nu- preventing autoimmunity. The development of autoimmune clear factor of activated T cells (NFAT), cAMP response ele- diseases is often associated with a decreased number of ment binding protein (CREB), and activating transcription CD4+CD25+ Tregs or a functional deficiency of these cells. factor (ATF), combine with the Foxp3 promoter or enhancer Several factors influence the CD4+CD25+ Treg number and and participate in Foxp3 regulation. The nuclear factor-kB function. Recent studies suggest that epigenetic mechanisms (NF-kB) signaling pathway induced by the TCR signaling may play an important role in regulating CD4+CD25+ Tregs. pathway is also involved in Treg differentiation. Themis1 and Vav1, newly identified members of the TCR signaling pathway, have been found to interact with each other and Characteristics and Functions of CD4+CD25+ Tregs impair Tregs suppressive functions, and modulate the occur- rence and development of inflammatory bowel disease [6]. In Classification and Markers of CD4+CD25+ Tregs addition, the CD28 signaling pathway plays an important role in the generation and maintenance of Tregs. Previous studies CD4+CD25+ Tregs account for 1 to 3 % of CD4+ T cells in have shown that the number of Foxp3+ T cells in the thymus human peripheral blood and 5 to 10 % of CD4+ T cells in and periphery is decreased to a large extent in the absence of murine lymph node and spleen. Currently, there are two rec- CD28 or its ligands, CD80 and CD86 (Fig. 1). ognized classes of CD4+CD25+ Treg cells, natural Tregs The interleukin-2 (IL-2) signaling pathway also plays an (nTregs), and induced Tregs (iTregs). nTregs develop in the important role in Treg development and immune function. It thymus and experience both positive and negative selection, has been demonstrated that IL-2 is obligatory for the differen- whereas iTregs are derived from the periphery. tiation, expression, and immunosuppressive function of Tregs CD4+CD25+ Tregs express a variety of proteins, such as [7]. Tregs exert suppressive effects on Th1, Th2, and Th17 cytotoxic T lymphocyte-associated antigen-4 (CTLA-4), tumor cells and contribute to the imbalance of the immunologic ho- necrosis factor receptor (TNFR) superfamily member, Toll-like meostasis between Tregs and effector Th cells, thus inhibiting receptor 4, C-X-C chemokine receptor type 4 (CXCR4), pro- the development of allergic and autoimmune reactions. TCR grammed death-1 (PD-1), and lymphocyte antigen complex 6. and CD28 signaling pathways alone do not sufficiently induce However, these proteins lack specificity because they are also Foxp3 expression. This indirect evidence comes from the ob- commonly expressed by activated effector T cells. servation of delayed Foxp3+ thymocytes after birth, while the Clinic Rev Allerg Immunol Fig. 1 Signaling pathways inducing the expression of Foxp3 in CD4+CD25+ Tregs. Signaling pathways play a key role in the differentiation of CD4+CD25+ Tregs through provoking Foxp3 induction and generation, which involve the TCR and CD28 signaling, interleukin-2 signaling, transforming growth factor-β signaling, and beta2-adrenergic receptor signaling CD4+CD25+Foxp3− thymocytes were easily detected. This cells and macrophages. IL-10 can inhibit the activation of may be because that Foxp3 induction and generation needs a monocytes and NK cells, IL-2 synthesis by Th1 cells, MHC- secondary signaling, namely, the IL-2 receptor (CD25). Lio II expression in dendritic cells and macrophages, and func- and Hsieh [8] presented a hypothesis on Treg differentiation: tions of antigen-presenting cells. Fibrinogen-like protein 2 is firstly, enhanced TCR signaling leads to increased expression another important inhibitory cytokine secreted by Tregs with of CD25 (alpha chain of IL-2 receptor), then the Treg precur- receptor-mediated immune suppression effects (Fig. 2). sors gain the ability to receive IL-2 signals, and finally induce the expression of Foxp3 through
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