5-Aza-2’-deoxycytidine may enhance the frequency of T regulatory cells from CD4⁺ naïve T cells isolated from the peripheral blood of patients with chronic HBV infection

References

• Sarin SK, Kumar M, Lau GK, et al. Asian-Pacific clinical practice guidelines on the management of hepatitis B: a 2015 update. Hepatol Int. 2016 Jan;10(1):1–98.
   PubMed Web of Science ®Google Scholar
• Choi YS, Lee J, Lee HW, et al. Liver injury in acute hepatitis A is associated with decreased frequency of regulatory T cells caused by Fas-mediated apoptosis. Gut. 2015;64(8):1303–1313.
   PubMed Web of Science ®Google Scholar
• Rehermann B. Chronic infections with hepatotropic viruses: mechanisms of impairment of cellular immune responses. Semin Liver Dis. 2007;27(2):152–160.
   PubMed Web of Science ®Google Scholar
• Stoop JN, van der Molen RG, Baan CC, et al. Regulatory T cells contribute to the impaired immune response in patients with chronic hepatitis B virus infection. Hepatology. 2005;41(4):771–778.
   PubMed Web of Science ®Google Scholar
• Xu D, Fu J, Jin L, et al. Circulating and liver resident CD4+CD25+ regulatory T cells actively influence the antiviral immune response and disease progression in patients with hepatitis B. J Iimmunol. 2006 Jul 1;177(1):739–747.
   PubMed Web of Science ®Google Scholar
• Komatsu N, Okamoto K, Sawa S, et al. Pathogenic conversion of Foxp3+ T cells into TH17 cells in autoimmune arthritis. Nat Med. 2014 Jan;20(1):62–68.
   PubMed Web of Science ®Google Scholar
• DuPage M, Bluestone JA. Harnessing the plasticity of CD4(+) T cells to treat immune-mediated disease. Nat Rev Immunol. 2016 Mar;16(3):149–163.
   PubMed Web of Science ®Google Scholar
• Zeybel M, Vatansever S, Hardy T, et al. DNA methylation profiling identifies novel markers of progression in hepatitis B-related chronic liver disease. Clin epigenetics. 2016;8:48.
   PubMed Web of Science ®Google Scholar
• Makar KW, Wilson CB. DNA methylation is a nonredundant repressor of the Th2 effector program. J Iimmunol. 2004 Oct 1;173(7):4402–4406.
   PubMed Web of Science ®Google Scholar
• Kelsey G, Stegle O, Reik W. Single-cell epigenomics: recording the past and predicting the future. Science. 2017 Oct 6;358(6359):69–75.
   PubMed Web of Science ®Google Scholar
• Jia D, Jurkowska RZ, Zhang X, et al. Structure of Dnmt3a bound to Dnmt3L suggests a model for de novo DNA methylation. Nature. 2007 Sep 13;449(7159):248–251.
   PubMed Web of Science ®Google Scholar
• Bettini ML, Pan F, Bettini M, et al. Loss of epigenetic modification driven by the Foxp3 transcription factor leads to regulatory T cell insufficiency. Immunity. 2012 May 25;36(5):717–730.
   PubMed Web of Science ®Google Scholar
• Zhao ZH, Fan YC, Zhao Q, et al. Promoter methylation status and expression of PPAR-gamma gene are associated with prognosis of acute-on-chronic hepatitis B liver failure. Clin epigenetics. 2015;7(1):115.
   PubMedGoogle Scholar
• Hu N, Fan XP, Fan YC, et al. Hypomethylated ubiquitin-conjugating enzyme2 Q1 (UBE2Q1) gene promoter in the serum is a promising biomarker for hepatitis B virus-associated hepatocellular carcinoma. Tohoku J Exp Med. 2017 Jun;242(2):93–100. .
   PubMed Web of Science ®Google Scholar
• Zhang JJ, Fan YC, Zhao ZH, et al. Prognoses of patients with acute-on-chronic hepatitis B liver failure are closely associated with altered SOCS1 mRNA expression and cytokine production following glucocorticoid treatment. Cell Mol Immunol. 2014 Jul;11(4):396–404.
   PubMed Web of Science ®Google Scholar
• Gao S, Sun FK, Fan YC, et al. Aberrant GSTP1 promoter methylation predicts short-term prognosis in acute-on-chronic hepatitis B liver failure. Aliment Pharmacol Ther. 2015 Aug;42(3):319–329.
   PubMed Web of Science ®Google Scholar
• Ohkura N, Hamaguchi M, Morikawa H, et al. T cell receptor stimulation-induced epigenetic changes and Foxp3 expression are independent and complementary events required for Treg cell development. Immunity. 2012 Nov 16;37(5):785–799.
   PubMed Web of Science ®Google Scholar
• Floess S, Freyer J, Siewert C, et al. Epigenetic control of the foxp3 locus in regulatory T cells. PLoS Biol. 2007 Feb;5(2):e38.
   PubMed Web of Science ®Google Scholar
• Egger G, Liang G, Aparicio A, et al. Epigenetics in human disease and prospects for epigenetic therapy. Nature. 2004 May 27;429(6990):457–463.
   PubMed Web of Science ®Google Scholar
• Omata M, Cheng AL, Kokudo N, et al. Asia-Pacific clinical practice guidelines on the management of hepatocellular carcinoma: a 2017 update. Hepatol Int. 2017 Jul;11(4):317–370.
   PubMed Web of Science ®Google Scholar
• World Medical A. World Medical Association Declaration of Helsinki: ethical principles for medical research involving human subjects. Jama. 2013 Nov 27;310(20):2191–2194.
   PubMed Web of Science ®Google Scholar
• McGrath-Morrow SA, Ndeh R, Helmin KA, et al. DNA methylation regulates the neonatal CD4(+) T-cell response to pneumonia in mice. J Biol Chem. 2018 Jul 27;293(30):11772–11783.
   PubMed Web of Science ®Google Scholar
• Slack A, Cervoni N, Pinard M, et al. Feedback regulation of DNA methyltransferase gene expression by methylation. Eur J Biochem. 1999;264(1):191–199.
   PubMedGoogle Scholar
• Yang G, Liu A, Xie Q, et al. Association of CD4+CD25+Foxp3+ regulatory T cells with chronic activity and viral clearance in patients with hepatitis B. Int Immunol. 2007 Feb;19(2):133–140.
   PubMed Web of Science ®Google Scholar
• Liu H, Komai-Koma M, Xu D, et al. Toll-like receptor 2 signaling modulates the functions of CD4+ CD25+ regulatory T cells. Proc Natl Acad Sci U S A. 2006;103(18):7048–7053. .
   PubMed Web of Science ®Google Scholar
• Su ZJ, Yu XP, Guo RY, et al. Changes in the balance between Treg and Th17 cells in patients with chronic hepatitis B. Diagn Microbiol Infect Dis. 2013;76(4):437–444. .
   PubMed Web of Science ®Google Scholar
• Yu X, Guo R, Ming D, et al. Ratios of regulatory T cells/T-helper 17 cells and transforming growth factor-beta1/interleukin-17 to be associated with the development of hepatitis B virus-associated liver cirrhosis. J Gastroenterol Hepatol. 2014 May;29(5):1065–1072.
   PubMed Web of Science ®Google Scholar
• Niu Y, Liu H, Yin D, et al. The balance between intrahepatic IL-17(+) T cells and Foxp3(+) regulatory T cells plays an important role in HBV-related end-stage liver disease. BMC immun. 2011;12(1):47.
   PubMedGoogle Scholar
• Yang H, Bueso-Ramos C, DiNardo C, et al. Expression of PD-L1, PD-L2, PD-1 and CTLA4 in myelodysplastic syndromes is enhanced by treatment with hypomethylating agents. Leukemia. 2014 Jun;28(6):1280–1288. .
   PubMed Web of Science ®Google Scholar
• Sun C, Fu B, Gao Y, et al. TGF-β1 down-regulation of NKG2D/DAP10 and 2B4/SAP expression on human NK cells contributes to HBV persistence. PLoS Pathog. 2012;8(3):e1002594.
   PubMed Web of Science ®Google Scholar
• Sabat R, Grutz G, Warszawska K, et al. Biology of interleukin-10. Cytokine Growth Factor Rev. 2010 Oct;21(5):331–344.
   PubMed Web of Science ®Google Scholar
• Shi M, Wei J, Dong J, et al. Function of interleukin-17 and −35 in the blood of patients with hepatitis B-related liver cirrhosis. Mol Med Rep. 2015 Jan;11(1):121–126.
   PubMed Web of Science ®Google Scholar
• Stross L, Gunther J, Gasteiger G, et al. Foxp3+ regulatory T cells protect the liver from immune damage and compromise virus control during acute experimental hepatitis B virus infection in mice. Hepatology. 2012 Sep;56(3):873–883.
   PubMed Web of Science ®Google Scholar
• Jiang R, Tang J, Chen Y, et al. The long noncoding RNA lnc-EGFR stimulates T-regulatory cells differentiation thus promoting hepatocellular carcinoma immune evasion. Nat Commun. 2017;8(1):15129.
   PubMedGoogle Scholar
• Nugent BM, Wright CL, Shetty AC, et al. Brain feminization requires active repression of masculinization via DNA methylation. Nat Neurosci. 2015;18(5):690–697.
   PubMed Web of Science ®Google Scholar
• Liu XS, Wu H, Ji X, et al. Editing DNA Methylation in the Mammalian Genome. Cell. 2016;167(1):233–247 e17. .
   PubMed Web of Science ®Google Scholar
• Stricker SH, Koferle A, Beck S. From profiles to function in epigenomics. Nat Rev Genet. 2017;18(1):51–66.
   PubMed Web of Science ®Google Scholar
• Sage PT, Francisco LM, Carman CV, et al. The receptor PD-1 controls follicular regulatory T cells in the lymph nodes and blood. Nat Immunol. 2013 Feb;14(2):152–161.
   PubMed Web of Science ®Google Scholar
• Wing K, Onishi Y, Prieto-Martin P, et al. CTLA-4 control over Foxp3+ regulatory T cell function. Science. 2008;322(5899):271–275.
   PubMed Web of Science ®Google Scholar
• Zhang B, Chikuma S, Hori S, et al. Nonoverlapping roles of PD-1 and FoxP3 in maintaining immune tolerance in a novel autoimmune pancreatitis mouse model. Proc Natl Acad Sci U S A. 2016;113(30):8490–8495.
   PubMed Web of Science ®Google Scholar
• Zheng Y, Josefowicz S, Chaudhry A, et al. Role of conserved non-coding DNA elements in the Foxp3 gene in regulatory T-cell fate. Nature. 2010;463(7282):808–812.
   PubMed Web of Science ®Google Scholar
• Sun X, Cui Y, Feng H, et al. TGF-beta signaling controls Foxp3 methylation and T reg cell differentiation by modulating Uhrf1 activity. J Exp Med. 2019 Dec 2;216(12):2819–2837
   PubMed Web of Science ®Google Scholar
• Fransolet G, Ehx G, Somja J, et al. Azacytidine mitigates experimental sclerodermic chronic graft-versus-host disease. J Hematol Oncol. 2016;9(1):53.
   PubMedGoogle Scholar
• Singer BD, Mock JR, Aggarwal NR, et al. Regulatory T cell DNA methyltransferase inhibition accelerates resolution of lung inflammation. Am J Respir Cell Mol Biol. 2015;52(5):641–652.
   PubMed Web of Science ®Google Scholar
• Choi J, Ritchey J, Prior JL, et al. In vivo administration of hypomethylating agents mitigate graft-versus-host disease without sacrificing graft-versus-leukemia. Blood. 2010;116(1):129–139.
   PubMed Web of Science ®Google Scholar
• Krop J, Heidt S, Claas FHJ, et al. Regulatory T cells in pregnancy: it is not all about foxP3. Front Immunol. 2020;11:1182.
   PubMed Web of Science ®Google Scholar
• Jamaleddine H, Santamaria P, Khadra A. Quantifying immunoregulation by autoantigen-specific T-regulatory type 1 cells in mice with simultaneous hepatic and extra-hepatic autoimmune disorders. Immunology. 2020 Nov;161(3):209–229.
   PubMed Web of Science ®Google Scholar
• Nocentini G, Cari L, Migliorati G. et al. The role of GITR single-positive cells in immune homeostasis. Immun Inflammation Dis. 2017;5(1):4–6.
   PubMed Web of Science ®Google Scholar