{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,16]],"date-time":"2026-10-16T01:03:02Z","timestamp":1792112582277,"version":"4.4.0"},"reference-count":116,"publisher":"MDPI AG","issue":"12","license":[{"start":{"date-parts":[[2021,12,8]],"date-time":"2021-12-08T00:00:00Z","timestamp":1638921600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/100000071","name":"Eunice Kennedy Shriver National Institute of Child Health and Human Development","doi-asserted-by":"publisher","award":["1ZIAHD001803-27"],"award-info":[{"award-number":["1ZIAHD001803-27"]}],"id":[{"id":"10.13039\/100000071","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Cells"],"abstract":"<jats:p>Immature CD4\u2212 CD8\u2212 thymocytes progress through several developmental steps in the thymus, ultimately emerging as mature CD4+ (helper) or CD8+ (cytotoxic) T cells. Activation of na\u00efve CD4+ and CD8+ T cells in the presence of specific cytokines results in the induction of transcriptional programs that result in their differentiation into effector or memory cells and in the case of CD4+ T cells, the adoption of distinct T-helper fates. Previous studies have shown that histone modification and DNA methylation play important roles in each of these events. More recently, the roles of specific epigenetic regulators in T cell differentiation have been clarified. The identification of the epigenetic modifications and modifiers that control mature T cell differentiation and specification has also provided further insights into how dysregulation of these processes can lead to cancer or autoimmune diseases. In this review, we summarize recent findings that have provided new insights into epigenetic regulation of T cell differentiation in both mice and humans.<\/jats:p>","DOI":"10.3390\/cells10123459","type":"journal-article","created":{"date-parts":[[2021,12,9]],"date-time":"2021-12-09T21:52:32Z","timestamp":1639086752000},"page":"3459","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":49,"title":["New Insights into Epigenetic Regulation of T Cell Differentiation"],"prefix":"10.3390","volume":"10","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-0368-2858","authenticated-orcid":false,"given":"Avik","family":"Dutta","sequence":"first","affiliation":[{"name":"Section on Hematopoiesis and Lymphocyte Biology, <i>Eunice Kennedy Shriver<\/i>, National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, MD 20892, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6831-6368","authenticated-orcid":false,"given":"Harini","family":"Venkataganesh","sequence":"additional","affiliation":[{"name":"Section on Hematopoiesis and Lymphocyte Biology, <i>Eunice Kennedy Shriver<\/i>, National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, MD 20892, USA"},{"name":"Rensselaer Polytechnic Institute, Troy, NY 12180, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Paul E.","family":"Love","sequence":"additional","affiliation":[{"name":"Section on Hematopoiesis and Lymphocyte Biology, <i>Eunice Kennedy Shriver<\/i>, National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, MD 20892, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2021,12,8]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"9","DOI":"10.1038\/nri2232","article-title":"Launching the T-cell-lineage developmental programme","volume":"8","author":"Rothenberg","year":"2008","journal-title":"Nat. Rev. Immunol."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"788","DOI":"10.1038\/nri2416","article-title":"Lineage fate and intense debate: Myths, models and mechanisms of CD4- versus CD8-lineage choice","volume":"8","author":"Singer","year":"2008","journal-title":"Nat. Rev. Immunol."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"735","DOI":"10.1016\/j.it.2021.06.005","article-title":"New insights into TCR \u03b2-selection","volume":"42","author":"Dutta","year":"2021","journal-title":"Trends Immunol."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"202","DOI":"10.1016\/j.immuni.2018.01.007","article-title":"Human T Cell Development, Localization, and Function throughout Life","volume":"48","author":"Kumar","year":"2018","journal-title":"Immunity"},{"key":"ref_5","doi-asserted-by":"crossref","unstructured":"Eriksson, J., D\u2019Angelo, W., and Badylak, S.F. (2019). Common Challenges in Tissue Regeneration, Elsevier.","DOI":"10.1016\/B978-0-12-814879-2.00009-1"},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"363","DOI":"10.1038\/s41577-018-0001-y","article-title":"The full spectrum of human naive T cells","volume":"18","author":"Borghans","year":"2018","journal-title":"Nat. Rev. Immunol."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"119","DOI":"10.3389\/fped.2016.00119","article-title":"Establishment and Maintenance of the Human Na\u00efve CD4+ T-Cell Compartment","volume":"4","author":"Silva","year":"2016","journal-title":"Front. Pediatrics"},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"445","DOI":"10.1146\/annurev-immunol-030409-101212","article-title":"Differentiation of effector CD4 T cell populations","volume":"28","author":"Zhu","year":"2010","journal-title":"Annu. Rev. Immunol."},{"key":"ref_9","first-page":"73","article-title":"Regulatory T cells (TREG) and their roles in immune system with respect to immunopathological disorders","volume":"53","author":"Krejsek","year":"2010","journal-title":"Acta Med."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"330","DOI":"10.1038\/ni904","article-title":"Foxp3 programs the development and function of CD4+CD25+ regulatory T cells","volume":"4","author":"Fontenot","year":"2003","journal-title":"Nat. Immunol."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"11","DOI":"10.1002\/eji.201444577","article-title":"Epigenetic control of thymic Treg-cell development","volume":"45","author":"Kitagawa","year":"2015","journal-title":"Eur. J. Immunol."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"685","DOI":"10.1038\/nature05673","article-title":"Foxp3 controls regulatory T-cell function by interacting with AML1\/Runx1","volume":"446","author":"Ono","year":"2007","journal-title":"Nature"},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"1010","DOI":"10.1038\/ni.2402","article-title":"Transcription factor Foxp3 and its protein partners form a complex regulatory network","volume":"13","author":"Rudra","year":"2012","journal-title":"Nat. Immunol."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"113","DOI":"10.1016\/j.jaut.2017.07.002","article-title":"Induction and maintenance of regulatory T cells by transcription factors and epigenetic modifications","volume":"83","author":"Nakatsukasa","year":"2017","journal-title":"J. Autoimmun."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"a007021","DOI":"10.1101\/cshperspect.a007021","article-title":"Treg cells, life history, and diversity","volume":"4","author":"Benoist","year":"2012","journal-title":"Cold Spring Harb. Perspect. Biol."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"29","DOI":"10.1016\/j.it.2019.11.008","article-title":"Epigenetic Regulation of T Cell Memory: Recalling Therapeutic Implications","volume":"41","author":"Tough","year":"2020","journal-title":"Trends Immunol."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"486","DOI":"10.1038\/nri3862","article-title":"Molecular and cellular insights into T cell exhaustion","volume":"15","author":"Wherry","year":"2015","journal-title":"Nat. Rev. Immunol."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"265","DOI":"10.1038\/s41586-019-1326-9","article-title":"TOX reinforces the phenotype and longevity of exhausted T cells in chronic viral infection","volume":"571","author":"Alfei","year":"2019","journal-title":"Nature"},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"1858","DOI":"10.3389\/fimmu.2017.01858","article-title":"Natural Killer T Cells: An Ecological Evolutionary Developmental Biology Perspective","volume":"8","author":"Kumar","year":"2017","journal-title":"Front. Immunol."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"564","DOI":"10.1016\/j.molimm.2018.08.020","article-title":"TET mediated epigenetic regulation of iNKT cell lineage fate choice and function","volume":"101","author":"Tsagaratou","year":"2018","journal-title":"Mol. Immunol."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"12","DOI":"10.1016\/j.cell.2012.06.013","article-title":"Cancer epigenetics: From mechanism to therapy","volume":"150","author":"Dawson","year":"2012","journal-title":"Cell"},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"707","DOI":"10.1016\/j.cell.2007.01.015","article-title":"The role of chromatin during transcription","volume":"128","author":"Li","year":"2007","journal-title":"Cell"},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"484","DOI":"10.1038\/nrg3230","article-title":"Functions of DNA methylation: Islands, start sites, gene bodies and beyond","volume":"13","author":"Jones","year":"2012","journal-title":"Nat. Rev. Genet."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"472","DOI":"10.1038\/nature12750","article-title":"TET enzymes, TDG and the dynamics of DNA demethylation","volume":"502","author":"Kohli","year":"2013","journal-title":"Nature"},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"34","DOI":"10.1186\/s13148-019-0632-2","article-title":"The emerging role of epigenetics in human autoimmune disorders","volume":"11","author":"Mazzone","year":"2019","journal-title":"Clin. Epigenetics"},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"128","DOI":"10.1007\/s12016-013-8401-z","article-title":"Epigenetic alterations and microRNA misexpresion in cancer and autoimmune diseases: A critical review","volume":"47","author":"Saito","year":"2014","journal-title":"Clin. Rev. Allergy Immunol."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"59","DOI":"10.1038\/s41580-019-0192-5","article-title":"Author Correction: Roles and regulation of histone methylation in animal development","volume":"21","author":"Jambhekar","year":"2020","journal-title":"Nat. Rev. Mol. Cell Biol."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"693","DOI":"10.1016\/j.cell.2007.02.005","article-title":"Chromatin modifications and their function","volume":"128","author":"Kouzarides","year":"2007","journal-title":"Cell"},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1016\/j.molcel.2006.12.010","article-title":"Dynamic regulation of histone lysine methylation by demethylases","volume":"25","author":"Shi","year":"2007","journal-title":"Mol. Cell"},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"19","DOI":"10.1016\/j.molonc.2007.01.001","article-title":"The role of histone deacetylases (HDACs) in human cancer","volume":"1","author":"Ropero","year":"2007","journal-title":"Mol. Oncol."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1038\/s41467-018-06186-1","article-title":"A bidentate Polycomb Repressive-Deubiquitinase complex is required for efficient activity on nucleosomes","volume":"9","author":"Foglizzo","year":"2018","journal-title":"Nat. Commun."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"728","DOI":"10.1016\/j.jaci.2018.07.014","article-title":"Epigenetic mechanisms regulating T-cell responses","volume":"142","author":"Schmidl","year":"2018","journal-title":"J. Allergy Clin. Immunol."},{"key":"ref_33","first-page":"w14191","article-title":"Epigenetics of T lymphocytes in health and disease","volume":"145","author":"Leoni","year":"2015","journal-title":"Swiss Med. Wkly."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1016\/bs.ai.2019.08.005","article-title":"Thymocyte selection: From signaling to epigenetic regulation","volume":"144","author":"Lyu","year":"2019","journal-title":"Adv. Immunol."},{"key":"ref_35","first-page":"953","article-title":"Dynamic Transcriptome, DNA Methylome, and DNA Hydroxymethylome Networks during T-Cell Lineage Commitment","volume":"41","author":"Yoon","year":"2018","journal-title":"Mol. Cells"},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"108505","DOI":"10.1016\/j.celrep.2020.108505","article-title":"The Methyltransferase DOT1L Controls Activation and Lineage Integrity in CD4+ T Cells during Infection and Inflammation","volume":"33","author":"Scheer","year":"2020","journal-title":"Cell Rep."},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"20706","DOI":"10.1073\/pnas.1920372117","article-title":"The histone methyltransferase DOT1L prevents antigen-independent differentiation and safeguards epigenetic identity of CD8+ T cells","volume":"117","author":"Aslam","year":"2020","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"1153","DOI":"10.4049\/jimmunol.1602129","article-title":"Menin Controls the Memory Th2 Cell Function by Maintaining the Epigenetic Integrity of Th2 Cells","volume":"199","author":"Onodera","year":"2017","journal-title":"J. Immunol."},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"799","DOI":"10.1038\/nrm3230","article-title":"Trithorax group proteins: Switching genes on and keeping them active","volume":"12","author":"Schuettengruber","year":"2011","journal-title":"Nat. Rev. Mol. Cell Biol."},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"394","DOI":"10.1016\/j.tibs.2013.05.005","article-title":"Menin: A scaffold protein that controls gene expression and cell signaling","volume":"38","author":"Matkar","year":"2013","journal-title":"Trends Biochem. Sci."},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"2493","DOI":"10.1084\/jem.20100760","article-title":"STAT6-mediated displacement of polycomb by trithorax complex establishes long-term maintenance of GATA3 expression in T helper type 2 cells","volume":"207","author":"Onodera","year":"2010","journal-title":"J. Exp. Med."},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"1280","DOI":"10.1182\/blood-2009-05-223255","article-title":"c-Myb, Menin, GATA-3, and MLL form a dynamic transcription complex that plays a pivotal role in human T helper type 2 cell development","volume":"116","author":"Nakata","year":"2010","journal-title":"Blood"},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"e20201690","DOI":"10.1084\/jem.20201690","article-title":"The Cxxc1 subunit of the Trithorax complex directs epigenetic licensing of CD4+ T cell differentiation","volume":"218","author":"Kiuchi","year":"2021","journal-title":"J. Exp. Med."},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"eaax1608","DOI":"10.1126\/sciadv.aax1608","article-title":"Epigenetic initiation of the TH17 differentiation program is promoted by Cxxc finger protein 1","volume":"5","author":"Lin","year":"2019","journal-title":"Sci. Adv."},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"34605","DOI":"10.1074\/jbc.M705100200","article-title":"IL-21 is produced by Th17 cells and drives IL-17 production in a STAT3-dependent manner","volume":"282","author":"Wei","year":"2007","journal-title":"J. Biol. Chem."},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"2306","DOI":"10.2741\/4054","article-title":"IL-6, IL-17 and STAT3: A holy trinity in auto-immunity?","volume":"17","author":"Camporeale","year":"2012","journal-title":"Front. Biosci. (Landmark Ed.)"},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"653","DOI":"10.1016\/j.celrep.2016.09.050","article-title":"ATF7IP-Mediated Stabilization of the Histone Methyltransferase SETDB1 Is Essential for Heterochromatin Formation by the HUSH Complex","volume":"17","author":"Timms","year":"2016","journal-title":"Cell Rep."},{"key":"ref_48","doi-asserted-by":"crossref","first-page":"2024","DOI":"10.1084\/jem.20182316","article-title":"The epigenetic regulator ATF7ip inhibits Il2 expression, regulating Th17 responses","volume":"216","author":"Sin","year":"2019","journal-title":"J. Exp. Med."},{"key":"ref_49","doi-asserted-by":"crossref","first-page":"6056","DOI":"10.1073\/pnas.1919893117","article-title":"Histone H3K27me3 demethylases regulate human Th17 cell development and effector functions by impacting on metabolism","volume":"117","author":"Cribbs","year":"2020","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_50","doi-asserted-by":"crossref","first-page":"297","DOI":"10.1084\/jem.20141499","article-title":"Coupling of T cell receptor specificity to natural killer T cell development by bivalent histone H3 methylation","volume":"212","author":"Dobenecker","year":"2015","journal-title":"J. Exp. Med."},{"key":"ref_51","doi-asserted-by":"crossref","first-page":"184","DOI":"10.1038\/ni.3644","article-title":"The histone demethylase UTX regulates the lineage-specific epigenetic program of invariant natural killer T cells","volume":"18","author":"Beyaz","year":"2017","journal-title":"Nat. Immunol."},{"key":"ref_52","doi-asserted-by":"crossref","first-page":"489","DOI":"10.1007\/s00251-019-01124-x","article-title":"Methylation of H3K27 and H3K4 in key gene promoter regions of thymus in RA mice is involved in the abnormal development and differentiation of iNKT cells","volume":"71","author":"Meng","year":"2019","journal-title":"Immunogenetics"},{"key":"ref_53","doi-asserted-by":"crossref","first-page":"1578","DOI":"10.4049\/jimmunol.1500435","article-title":"Histone Deacetylase 3 Is Required for T Cell Maturation","volume":"195","author":"Hsu","year":"2015","journal-title":"J. Immunol."},{"key":"ref_54","doi-asserted-by":"crossref","first-page":"1582","DOI":"10.1038\/ncomms2580","article-title":"The transcriptional repressor NKAP is required for the development of iNKT cells","volume":"4","author":"Thapa","year":"2013","journal-title":"Nat. Commun."},{"key":"ref_55","doi-asserted-by":"crossref","first-page":"e20191453","DOI":"10.1084\/jem.20191453","article-title":"Hdac3 is an epigenetic inhibitor of the cytotoxicity program in CD8 T cells","volume":"217","author":"Tay","year":"2020","journal-title":"J. Exp. Med."},{"key":"ref_56","doi-asserted-by":"crossref","first-page":"695","DOI":"10.1038\/ni.3456","article-title":"Tcf1 and Lef1 transcription factors establish CD8+ T cell identity through intrinsic HDAC activity","volume":"17","author":"Xing","year":"2016","journal-title":"Nat. Immunol."},{"key":"ref_57","doi-asserted-by":"crossref","first-page":"3927","DOI":"10.4049\/jimmunol.1600312","article-title":"The Histone Acetyltransferase Gcn5 Positively Regulates T Cell Activation","volume":"198","author":"Gao","year":"2017","journal-title":"J. Immunol."},{"key":"ref_58","doi-asserted-by":"crossref","first-page":"600","DOI":"10.1016\/j.celrep.2017.06.065","article-title":"The Lysine Acetyltransferase GCN5 Is Required for iNKT Cell Development through EGR2 Acetylation","volume":"20","author":"Wang","year":"2017","journal-title":"Cell Rep."},{"key":"ref_59","doi-asserted-by":"crossref","first-page":"1830","DOI":"10.1172\/JCI131375","article-title":"Inhibiting the coregulator CoREST impairs Foxp3+ Treg function and promotes antitumor immunity","volume":"130","author":"Xiong","year":"2020","journal-title":"J. Clin. Investig."},{"key":"ref_60","doi-asserted-by":"crossref","first-page":"53","DOI":"10.1038\/s41467-017-02242-4","article-title":"Targeting the CoREST complex with dual histone deacetylase and demethylase inhibitors","volume":"9","author":"Kalin","year":"2018","journal-title":"Nat. Commun."},{"key":"ref_61","doi-asserted-by":"crossref","first-page":"596","DOI":"10.1016\/j.immuni.2017.03.012","article-title":"Polycomb Repressive Complex 2-Mediated Chromatin Repression Guides Effector CD8+ T Cell Terminal Differentiation and Loss of Multipotency","volume":"46","author":"Gray","year":"2017","journal-title":"Immunity"},{"key":"ref_62","doi-asserted-by":"crossref","first-page":"390","DOI":"10.1038\/s41388-018-0451-5","article-title":"Inhibition of histone lysine-specific demethylase 1 elicits breast tumor immunity and enhances antitumor efficacy of immune checkpoint blockade","volume":"38","author":"Qin","year":"2019","journal-title":"Oncogene"},{"key":"ref_63","doi-asserted-by":"crossref","first-page":"1228","DOI":"10.3389\/fimmu.2020.01228","article-title":"Targeting Nuclear LSD1 to Reprogram Cancer Cells and Reinvigorate Exhausted T Cells via a Novel LSD1-EOMES Switch","volume":"11","author":"Tu","year":"2020","journal-title":"Front. Immunol."},{"key":"ref_64","doi-asserted-by":"crossref","first-page":"549","DOI":"10.1016\/j.cell.2018.05.052","article-title":"LSD1 Ablation Stimulates Anti-tumor Immunity and Enables Checkpoint Blockade","volume":"174","author":"Sheng","year":"2018","journal-title":"Cell"},{"key":"ref_65","doi-asserted-by":"crossref","first-page":"211","DOI":"10.1038\/s41586-019-1325-x","article-title":"TOX transcriptionally and epigenetically programs CD8+ T cell exhaustion","volume":"571","author":"Khan","year":"2019","journal-title":"Nature"},{"key":"ref_66","doi-asserted-by":"crossref","first-page":"12410","DOI":"10.1073\/pnas.1905675116","article-title":"TOX and TOX2 transcription factors cooperate with NR4A transcription factors to impose CD8+ T cell exhaustion","volume":"116","author":"Seo","year":"2019","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_67","doi-asserted-by":"crossref","first-page":"270","DOI":"10.1038\/s41586-019-1324-y","article-title":"TOX is a critical regulator of tumour-specific T cell differentiation","volume":"571","author":"Scott","year":"2019","journal-title":"Nature"},{"key":"ref_68","doi-asserted-by":"crossref","first-page":"6180","DOI":"10.4049\/jimmunol.1300181","article-title":"Recent thymic emigrants and mature naive T cells exhibit differential DNA methylation at key cytokine loci","volume":"190","author":"Berkley","year":"2013","journal-title":"J. Immunol."},{"key":"ref_69","doi-asserted-by":"crossref","first-page":"2987","DOI":"10.1084\/jem.20090934","article-title":"GATA-3 is required for early T lineage progenitor development","volume":"206","author":"Hosoya","year":"2009","journal-title":"J. Exp. Med."},{"key":"ref_70","doi-asserted-by":"crossref","first-page":"233","DOI":"10.1016\/j.it.2014.04.002","article-title":"GATA3: A master of many trades in immune regulation","volume":"35","author":"Wan","year":"2014","journal-title":"Trends Immunol."},{"key":"ref_71","doi-asserted-by":"crossref","first-page":"415","DOI":"10.1093\/intimm\/dxr029","article-title":"An updated view on transcription factor GATA3-mediated regulation of Th1 and Th2 cell differentiation","volume":"23","author":"Yagi","year":"2011","journal-title":"Int. Immunol."},{"key":"ref_72","doi-asserted-by":"crossref","first-page":"594","DOI":"10.2174\/1566524019666190126112238","article-title":"The Bromodomain and Extra-Terminal Protein Inhibitor OTX015 Suppresses T Helper Cell Proliferation and Differentiation","volume":"18","author":"Hu","year":"2019","journal-title":"Curr. Mol. Med."},{"key":"ref_73","doi-asserted-by":"crossref","first-page":"1664","DOI":"10.1084\/jem.20190337","article-title":"The E3 ligase VHL promotes follicular helper T cell differentiation via glycolytic-epigenetic control","volume":"216","author":"Zhu","year":"2019","journal-title":"J. Exp. Med."},{"key":"ref_74","doi-asserted-by":"crossref","first-page":"S42","DOI":"10.1097\/ICO.0000000000001720","article-title":"Development and Functional Modulation of Regulatory T Cells by Transcription Factors and Epigenetics","volume":"37","author":"Ito","year":"2018","journal-title":"Cornea"},{"key":"ref_75","doi-asserted-by":"crossref","unstructured":"Bellanti, J.A., and Li, D. (2021). Treg Cells and Epigenetic Regulation, Springer.","DOI":"10.1007\/978-981-15-6407-9_6"},{"key":"ref_76","doi-asserted-by":"crossref","first-page":"24","DOI":"10.1111\/imm.13178","article-title":"Control of regulatory T-cell differentiation and function by T-cell receptor signalling and Foxp3 transcription factor complexes","volume":"160","author":"Ono","year":"2020","journal-title":"Immunology"},{"key":"ref_77","doi-asserted-by":"crossref","first-page":"465","DOI":"10.1038\/s41422-020-0324-7","article-title":"Transcriptional and epigenetic basis of Treg cell development and function: Its genetic anomalies or variations in autoimmune diseases","volume":"30","author":"Ohkura","year":"2020","journal-title":"Cell Res."},{"key":"ref_78","doi-asserted-by":"crossref","first-page":"104026","DOI":"10.1016\/j.cellimm.2019.104026","article-title":"Epigenetic and transcriptional analysis supports human regulatory T cell commitment at the CD4+CD8+ thymocyte stage","volume":"347","author":"Vanhanen","year":"2020","journal-title":"Cell. Immunol."},{"key":"ref_79","doi-asserted-by":"crossref","first-page":"488","DOI":"10.3389\/fimmu.2016.00488","article-title":"DNA Methyltransferase Inhibitor Promotes Human CD4+CD25hFOXP3+ Regulatory T Lymphocyte Induction under Suboptimal TCR Stimulation","volume":"7","author":"Lu","year":"2016","journal-title":"Front. Immunol."},{"key":"ref_80","doi-asserted-by":"crossref","first-page":"6571","DOI":"10.1172\/JCI137712","article-title":"Maintenance DNA methylation is essential for regulatory T cell development and stability of suppressive function","volume":"130","author":"Helmin","year":"2020","journal-title":"J. Clin. Investig."},{"key":"ref_81","doi-asserted-by":"crossref","first-page":"749","DOI":"10.1016\/j.cell.2014.07.031","article-title":"Control of the inheritance of regulatory T cell identity by a cis element in the Foxp3 locus","volume":"158","author":"Feng","year":"2014","journal-title":"Cell"},{"key":"ref_82","doi-asserted-by":"crossref","first-page":"734","DOI":"10.1016\/j.cell.2014.07.030","article-title":"Function of a Foxp3 cis-element in protecting regulatory T cell identity","volume":"158","author":"Li","year":"2014","journal-title":"Cell"},{"key":"ref_83","doi-asserted-by":"crossref","first-page":"442","DOI":"10.1016\/j.cell.2013.06.044","article-title":"CRISPR-mediated modular RNA-guided regulation of transcription in eukaryotes","volume":"154","author":"Gilbert","year":"2013","journal-title":"Cell"},{"key":"ref_84","doi-asserted-by":"crossref","first-page":"2953","DOI":"10.4049\/jimmunol.2000537","article-title":"Cutting Edge: CRISPR-Based Transcriptional Regulators Reveal Transcription-Dependent Establishment of Epigenetic Memory of Foxp3 in Regulatory T Cells","volume":"205","author":"Cameron","year":"2020","journal-title":"J. Immunol."},{"key":"ref_85","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1038\/s41467-018-07806-6","article-title":"Interleukin 2 modulates thymic-derived regulatory T cell epigenetic landscape","volume":"9","author":"Chorro","year":"2018","journal-title":"Nat. Commun."},{"key":"ref_86","doi-asserted-by":"crossref","first-page":"1270","DOI":"10.1038\/ni1117-1270a","article-title":"Addendum: Guidance of regulatory T cell development by Satb1-dependent super-enhancer establishment","volume":"18","author":"Kitagawa","year":"2017","journal-title":"Nat. Immunol."},{"key":"ref_87","doi-asserted-by":"crossref","first-page":"1101","DOI":"10.1084\/jem.20170084","article-title":"Signaling function of PRC2 is essential for TCR-driven T cell responses","volume":"215","author":"Dobenecker","year":"2018","journal-title":"J. Exp. Med."},{"key":"ref_88","doi-asserted-by":"crossref","first-page":"e140755","DOI":"10.1172\/JCI140755","article-title":"BMI1 maintains the Treg epigenomic landscape to prevent inflammatory bowel disease","volume":"131","author":"Gonzalez","year":"2021","journal-title":"J. Clin. Investig."},{"key":"ref_89","doi-asserted-by":"crossref","first-page":"228","DOI":"10.1038\/nature23475","article-title":"Metabolic control of TH17 and induced Treg cell balance by an epigenetic mechanism","volume":"548","author":"Xu","year":"2017","journal-title":"Nature"},{"key":"ref_90","doi-asserted-by":"crossref","first-page":"573","DOI":"10.1038\/ni.3706","article-title":"Epigenetic landscapes reveal transcription factors that regulate CD8+ T cell differentiation","volume":"18","author":"Yu","year":"2017","journal-title":"Nat. Immunol."},{"key":"ref_91","doi-asserted-by":"crossref","first-page":"585168","DOI":"10.3389\/fimmu.2020.585168","article-title":"Distinct Age-Related Epigenetic Signatures in CD4 and CD8 T Cells","volume":"11","author":"Hu","year":"2020","journal-title":"Front. Immunol."},{"key":"ref_92","first-page":"346","article-title":"Corrigendum: Regulation of T Cell Differentiation and Function by EZH2","volume":"7","author":"Karantanos","year":"2016","journal-title":"Front. Immunol."},{"key":"ref_93","doi-asserted-by":"crossref","first-page":"593203","DOI":"10.3389\/fimmu.2020.593203","article-title":"EZH2 as a Regulator of CD8+ T Cell Fate and Function","volume":"11","author":"Stairiker","year":"2020","journal-title":"Front. Immunol."},{"key":"ref_94","doi-asserted-by":"crossref","first-page":"1864","DOI":"10.1126\/science.273.5283.1864","article-title":"Requirement for CD40 ligand in costimulation induction, T cell activation, and experimental allergic encephalomyelitis","volume":"273","author":"Grewal","year":"1996","journal-title":"Science"},{"key":"ref_95","doi-asserted-by":"crossref","first-page":"327","DOI":"10.1189\/jlb.1A0915-396RR","article-title":"ThPOK represses CXXC5, which induces methylation of histone H3 lysine 9 in Cd40lg promoter by association with SUV39H1: Implications in repression of CD40L expression in CD8+ cytotoxic T cells","volume":"100","author":"Tsuchiya","year":"2016","journal-title":"J. Leukoc. Biol."},{"key":"ref_96","doi-asserted-by":"crossref","first-page":"283","DOI":"10.1016\/j.immuni.2009.06.021","article-title":"Blimp-1 transcription factor is required for the differentiation of effector CD8+ T cells and memory responses","volume":"31","author":"Kallies","year":"2009","journal-title":"Immunity"},{"key":"ref_97","doi-asserted-by":"crossref","first-page":"2397","DOI":"10.1074\/jbc.RA118.006977","article-title":"Histone acetyltransferase CBP is critical for conventional effector and memory T-cell differentiation in mice","volume":"294","author":"Piccirillo","year":"2019","journal-title":"J. Biol. Chem."},{"key":"ref_98","doi-asserted-by":"crossref","first-page":"82","DOI":"10.4049\/jimmunol.1700559","article-title":"The Loss of TET2 Promotes CD8+ T Cell Memory Differentiation","volume":"200","author":"Carty","year":"2018","journal-title":"J. Immunol."},{"key":"ref_99","doi-asserted-by":"crossref","first-page":"404","DOI":"10.1038\/nature25144","article-title":"Effector CD8 T cells dedifferentiate into long-lived memory cells","volume":"552","author":"Youngblood","year":"2017","journal-title":"Nature"},{"key":"ref_100","doi-asserted-by":"crossref","first-page":"10631","DOI":"10.1073\/pnas.1524490113","article-title":"De novo DNA methylation by DNA methyltransferase 3a controls early effector CD8+ T-cell fate decisions following activation","volume":"113","author":"Ladle","year":"2016","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_101","doi-asserted-by":"crossref","first-page":"1148","DOI":"10.1016\/j.immuni.2016.10.022","article-title":"Epigenomic Profiling of Human CD4+ T Cells Supports a Linear Differentiation Model and Highlights Molecular Regulators of Memory Development","volume":"45","author":"Durek","year":"2016","journal-title":"Immunity"},{"key":"ref_102","doi-asserted-by":"crossref","first-page":"177","DOI":"10.1126\/science.aah6499","article-title":"The epigenetic control of stemness in CD8+ T cell fate commitment","volume":"359","author":"Pace","year":"2018","journal-title":"Science"},{"key":"ref_103","doi-asserted-by":"crossref","first-page":"e2013452118","DOI":"10.1073\/pnas.2013452118","article-title":"E2A-regulated epigenetic landscape promotes memory CD8 T cell differentiation","volume":"118","author":"Schauder","year":"2021","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_104","doi-asserted-by":"crossref","first-page":"1214","DOI":"10.1038\/s41418-019-0410-x","article-title":"T-cell receptor signal strength and epigenetic control of Bim predict memory CD8+ T-cell fate","volume":"27","author":"Li","year":"2020","journal-title":"Cell Death Differ."},{"key":"ref_105","doi-asserted-by":"crossref","first-page":"2856","DOI":"10.1172\/JCI123801","article-title":"USP16-mediated deubiquitination of calcineurin A controls peripheral T cell maintenance","volume":"129","author":"Zhang","year":"2019","journal-title":"J. Clin. Investig."},{"key":"ref_106","doi-asserted-by":"crossref","first-page":"18","DOI":"10.1038\/s41556-019-0440-0","article-title":"Ketogenesis-generated \u03b2-hydroxybutyrate is an epigenetic regulator of CD8+ T-cell memory development","volume":"22","author":"Zhang","year":"2020","journal-title":"Nat. Cell Biol."},{"key":"ref_107","doi-asserted-by":"crossref","unstructured":"Mak, T.W., and Saunders, M.E. (2006). Bridging Innate and Adaptive Immunity: NK, \u03b3\u03b4 T, and NKT Cells, Elsevier.","DOI":"10.1016\/B978-012088451-3.50020-X"},{"key":"ref_108","doi-asserted-by":"crossref","first-page":"549","DOI":"10.1016\/j.jaci.2019.02.024","article-title":"Ezh2 controls development of natural killer T cells, which cause spontaneous asthma-like pathology","volume":"144","author":"Tumes","year":"2019","journal-title":"J. Allergy Clin. Immunol."},{"key":"ref_109","doi-asserted-by":"crossref","first-page":"5007","DOI":"10.1038\/onc.2012.8","article-title":"Dynamic interaction between TAL1 oncoprotein and LSD1 regulates TAL1 function in hematopoiesis and leukemogenesis","volume":"31","author":"Li","year":"2012","journal-title":"Oncogene"},{"key":"ref_110","doi-asserted-by":"crossref","first-page":"574","DOI":"10.1002\/ijc.25349","article-title":"Overexpression of LSD1 contributes to human carcinogenesis through chromatin regulation in various cancers","volume":"128","author":"Hayami","year":"2011","journal-title":"Int. J. Cancer"},{"key":"ref_111","doi-asserted-by":"crossref","first-page":"1227","DOI":"10.4155\/fmc-2017-0068","article-title":"Advances toward LSD1 inhibitors for cancer therapy","volume":"9","author":"Fu","year":"2017","journal-title":"Future Med. Chem."},{"key":"ref_112","doi-asserted-by":"crossref","first-page":"3735","DOI":"10.1158\/0008-5472.CAN-11-4136","article-title":"NF-\u03baB hyperactivation in tumor tissues allows tumor-selective reprogramming of the chemokine microenvironment to enhance the recruitment of cytolytic T effector cells","volume":"72","author":"Muthuswamy","year":"2012","journal-title":"Cancer Res."},{"key":"ref_113","doi-asserted-by":"crossref","first-page":"1469","DOI":"10.1016\/j.molcel.2021.01.038","article-title":"DNA hypomethylating agents increase activation and cytolytic activity of CD8+ T cells","volume":"81","author":"Bell","year":"2021","journal-title":"Mol. Cell"},{"key":"ref_114","doi-asserted-by":"crossref","first-page":"340","DOI":"10.1038\/nri.2017.146","article-title":"Epigenetic control of CD8+ T cell differentiation","volume":"18","author":"Henning","year":"2018","journal-title":"Nat. Rev. Immunol."},{"key":"ref_115","doi-asserted-by":"crossref","first-page":"452","DOI":"10.1038\/nature22367","article-title":"Chromatin states define tumour-specific T cell dysfunction and reprogramming","volume":"545","author":"Philip","year":"2017","journal-title":"Nature"},{"key":"ref_116","doi-asserted-by":"crossref","first-page":"50","DOI":"10.1111\/imr.12237","article-title":"Epigenetics in T-cell acute lymphoblastic leukemia","volume":"263","author":"Peirs","year":"2015","journal-title":"Immunol. Rev."}],"container-title":["Cells"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2073-4409\/10\/12\/3459\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,11]],"date-time":"2025-10-11T07:43:17Z","timestamp":1760168597000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2073-4409\/10\/12\/3459"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2021,12,8]]},"references-count":116,"journal-issue":{"issue":"12","published-online":{"date-parts":[[2021,12]]}},"alternative-id":["cells10123459"],"URL":"https:\/\/doi.org\/10.3390\/cells10123459","relation":{},"ISSN":["2073-4409"],"issn-type":[{"value":"2073-4409","type":"electronic"}],"subject":[],"published":{"date-parts":[[2021,12,8]]}}}