{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,27]],"date-time":"2026-09-27T05:10:10Z","timestamp":1790485810012,"version":"4.1.0"},"reference-count":99,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2022,3,31]],"date-time":"2022-03-31T00:00:00Z","timestamp":1648684800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100001809","name":"National Natural Science Foundation of China","doi-asserted-by":"publisher","id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Immunol."],"abstract":"<jats:p>\n                    CD4\n                    <jats:sup>+<\/jats:sup>\n                    CD25\n                    <jats:sup>+<\/jats:sup>\n                    Foxp3\n                    <jats:sup>+<\/jats:sup>\n                    Regulatory (Treg) T cells are mainly generated within the thymus. However, the mechanism of thymic Treg cell (tTreg cell) generation remains to be fully revealed. Although the functions of TCR\/CD28 co-stimulation have been widely accepted, the functions of cytokines in the generation of tTreg cells remain highly controversial. In this review, we summarize the existing studies on cytokine regulation of tTreg cell generation. By integrating the key findings of cytokines in tTreg cell generation, we have concluded that four members of \u03b3c family cytokines (IL-2, IL-4, IL-7 and IL-15), transforming growth factor \u03b2 (TGF-\u03b2), and three members of TNF superfamily cytokines (GITRL, OX40L and TNF-\u03b1) play vitally important roles in regulating tTreg cell generation. We also point out all disputed points and highlight critical scientific questions that need to be addressed in the future.\n                  <\/jats:p>","DOI":"10.3389\/fimmu.2022.883560","type":"journal-article","created":{"date-parts":[[2022,3,31]],"date-time":"2022-03-31T05:56:34Z","timestamp":1648706194000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":9,"title":["Role of Cytokines in Thymic Regulatory T Cell Generation: Overview and Updates"],"prefix":"10.3389","volume":"13","author":[{"given":"Mei","family":"Tang","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Fuya","family":"Jia","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Fang","family":"Nan","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Fengqiong","family":"Zuo","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zhu","family":"Yuan","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Dunfang","family":"Zhang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2022,3,31]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","DOI":"10.1016\/s0092-8674(00)80856-9","article-title":"Regulatory T Cells: Key Controllers of Immunologic Self-Tolerance","volume":"101","author":"Sakaguchi","year":"2000","journal-title":"Cell"},{"key":"B2","doi-asserted-by":"crossref","DOI":"10.4049\/jimmunol.155.3.1151","article-title":"Immunologic Self-Tolerance Maintained by Activated T Cells Expressing IL-2 Receptor Alpha-Chains (CD25). Breakdown of a Single Mechanism of Self-Tolerance Causes Various Autoimmune Diseases","volume":"155","author":"Sakaguchi","year":"1995","journal-title":"J Immunol"},{"key":"B3","doi-asserted-by":"publisher","DOI":"10.1126\/science.1079490","article-title":"Control of Regulatory T Cell Development by the Transcription Factor Foxp3","volume":"299","author":"Hori","year":"2003","journal-title":"Science"},{"key":"B4","doi-asserted-by":"publisher","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":"B5","doi-asserted-by":"publisher","DOI":"10.1038\/ni909","article-title":"An Essential Role for Scurfin in CD4+CD25+ T Regulatory Cells","volume":"4","author":"Khattri","year":"2003","journal-title":"Nat Immunol"},{"key":"B6","doi-asserted-by":"publisher","DOI":"10.1016\/s1074-7613(02)00367-9","article-title":"CD4 Regulatory T Cells Prevent Lethal Autoimmunity in IL-2Rbeta-Deficient Mice. Implications for the Nonredundant Function of IL-2","volume":"17","author":"Malek","year":"2002","journal-title":"Immunity"},{"key":"B7","doi-asserted-by":"publisher","DOI":"10.2217\/imt.15.79","article-title":"Manipulating Regulatory T Cells: A Promising Strategy to Treat Autoimmunity","volume":"7","author":"Zhang","year":"2015","journal-title":"Immunotherapy"},{"key":"B8","doi-asserted-by":"publisher","DOI":"10.1146\/annurev.immunol.21.120601.141122","article-title":"Naturally Arising CD4+ Regulatory T Cells for Immunologic Self-Tolerance and Negative Control of Immune Responses","volume":"22","author":"Sakaguchi","year":"2004","journal-title":"Annu Rev Immunol"},{"key":"B9","doi-asserted-by":"publisher","DOI":"10.1038\/nature12079","article-title":"Thymus-Derived Regulatory T Cells Contribute to Tolerance to Commensal Microbiota","volume":"497","author":"Cebula","year":"2013","journal-title":"Nature"},{"key":"B10","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.0909122107","article-title":"Inducible Foxp3+ Regulatory T-Cell Development by a Commensal Bacterium of the Intestinal Microbiota","volume":"107","author":"Round","year":"2010","journal-title":"Proc Natl Acad Sci USA"},{"key":"B11","doi-asserted-by":"publisher","DOI":"10.1038\/ni1037","article-title":"Regulatory T Cells Mediate Maternal Tolerance to the Fetus","volume":"5","author":"Aluvihare","year":"2004","journal-title":"Nat Immunol"},{"key":"B12","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.1003909107","article-title":"Pregnancy Induces a Fetal Antigen-Specific Maternal T Regulatory Cell Response That Contributes to Tolerance","volume":"107","author":"Kahn","year":"2010","journal-title":"Proc Natl Acad Sci USA"},{"key":"B13","doi-asserted-by":"publisher","DOI":"10.1172\/JCI39387","article-title":"Tregs Control the Development of Symptomatic West Nile Virus Infection in Humans and Mice","volume":"119","author":"Lanteri","year":"2009","journal-title":"J Clin Invest"},{"key":"B14","doi-asserted-by":"publisher","DOI":"10.1016\/j.immuni.2009.10.001","article-title":"Decrease of Foxp3+ Treg Cell Number and Acquisition of Effector Cell Phenotype During Lethal Infection","volume":"31","author":"Oldenhove","year":"2009","journal-title":"Immunity"},{"key":"B15","doi-asserted-by":"publisher","DOI":"10.1172\/JCI31202","article-title":"Tregs and Rethinking Cancer Immunotherapy","volume":"117","author":"Curiel","year":"2007","journal-title":"J Clin Invest"},{"key":"B16","doi-asserted-by":"publisher","DOI":"10.1038\/cr.2016.151","article-title":"Regulatory T Cells in Cancer Immunotherapy","volume":"27","author":"Tanaka","year":"2017","journal-title":"Cell Res"},{"key":"B17","doi-asserted-by":"publisher","first-page":"88","DOI":"10.1111\/imr.12160","article-title":"Ttregs, Ptregs, and Itregs: Similarities and Differences","volume":"259","author":"Shevach","year":"2014","journal-title":"Immunol Rev"},{"key":"B18","doi-asserted-by":"publisher","DOI":"10.1038\/86302","article-title":"Thymic Selection of CD4+CD25+ Regulatory T Cells Induced by an Agonist Self-Peptide","volume":"2","author":"Jordan","year":"2001","journal-title":"Nat Immunol"},{"key":"B19","doi-asserted-by":"publisher","DOI":"10.1038\/ni816","article-title":"Origin of Regulatory T Cells With Known Specificity for Antigen","volume":"3","author":"Apostolou","year":"2002","journal-title":"Nat Immunol"},{"key":"B20","doi-asserted-by":"publisher","DOI":"10.1038\/ni1160","article-title":"CD28 Costimulation of Developing Thymocytes Induces Foxp3 Expression and Regulatory T Cell Differentiation Independently of Interleukin 2","volume":"6","author":"Tai","year":"2005","journal-title":"Nat Immunol"},{"key":"B21","doi-asserted-by":"publisher","first-page":"95","DOI":"10.1146\/annurev-immunol-020711-075035","article-title":"Selection of Self-Reactive T Cells in the Thymus","volume":"30","author":"Stritesky","year":"2012","journal-title":"Annu Rev Immunol"},{"key":"B22","doi-asserted-by":"publisher","DOI":"10.1002\/eji.201343767","article-title":"Strength of TCR Signal From Self-Peptide Modulates Autoreactive Thymocyte Deletion and Foxp3(+) Treg-Cell Formation","volume":"44","author":"Caton","year":"2014","journal-title":"Eur J Immunol"},{"key":"B23","doi-asserted-by":"publisher","DOI":"10.1038\/nri3155","article-title":"Selection of Regulatory T Cells in the Thymus","volume":"12","author":"Hsieh","year":"2012","journal-title":"Nat Rev Immunol"},{"key":"B24","doi-asserted-by":"publisher","DOI":"10.1016\/j.immuni.2012.07.009","article-title":"A Broad Range of Self-Reactivity Drives Thymic Regulatory T Cell Selection to Limit Responses to Self","volume":"37","author":"Lee","year":"2012","journal-title":"Immunity"},{"key":"B25","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.1320319111","article-title":"Thymocyte Apoptosis Drives the Intrathymic Generation of Regulatory T Cells","volume":"111","author":"Konkel","year":"2014","journal-title":"Proc Natl Acad Sci USA"},{"key":"B26","doi-asserted-by":"publisher","DOI":"10.1016\/j.immuni.2007.11.021","article-title":"A Two-Step Process for Thymic Regulatory T Cell Development","volume":"28","author":"Lio","year":"2008","journal-title":"Immunity"},{"key":"B27","doi-asserted-by":"publisher","DOI":"10.1016\/j.immuni.2007.11.022","article-title":"Linked T Cell Receptor and Cytokine Signaling Govern the Development of the Regulatory T Cell Repertoire","volume":"28","author":"Burchill","year":"2008","journal-title":"Immunity"},{"key":"B28","doi-asserted-by":"publisher","DOI":"10.1016\/j.immuni.2013.02.022","article-title":"Foxp3 Transcription Factor is Proapoptotic and Lethal to Developing Regulatory T Cells Unless Counterbalanced by Cytokine Survival Signals","volume":"38","author":"Tai","year":"2013","journal-title":"Immunity"},{"key":"B29","doi-asserted-by":"publisher","DOI":"10.4161\/cc.27787","article-title":"Basis of Treg Development in the Thymus","volume":"13","author":"Tai","year":"2014","journal-title":"Cell Cycle"},{"key":"B30","doi-asserted-by":"publisher","first-page":"195","DOI":"10.1038\/s41590-018-0289-6","article-title":"Thymic Regulatory T Cells Arise via Two Distinct Developmental Programs","volume":"20","author":"Owen","year":"2019","journal-title":"Nat Immunol"},{"key":"B31","doi-asserted-by":"publisher","DOI":"10.1038\/ni.2849","article-title":"Costimulation via the Tumor-Necrosis Factor Receptor Superfamily Couples TCR Signal Strength to the Thymic Differentiation of Regulatory T Cells","volume":"15","author":"Mahmud","year":"2014","journal-title":"Nat Immunol"},{"key":"B32","doi-asserted-by":"publisher","DOI":"10.1038\/ni.1607","article-title":"A Critical Function for TGF-Beta Signaling in the Development of Natural CD4+CD25+Foxp3+ Regulatory T Cells","volume":"9","author":"Liu","year":"2008","journal-title":"Nat Immunol"},{"key":"B33","doi-asserted-by":"publisher","DOI":"10.1038\/352621a0","article-title":"Development and Function of T Cells in Mice Rendered Interleukin-2 Deficient by Gene Targeting","volume":"352","author":"Schorle","year":"1991","journal-title":"Nature"},{"key":"B34","doi-asserted-by":"publisher","DOI":"10.1016\/0092-8674(93)80067-o","article-title":"Ulcerative Colitis-Like Disease in Mice With a Disrupted Interleukin-2 Gene","volume":"75","author":"Sadlack","year":"1993","journal-title":"Cell"},{"key":"B35","doi-asserted-by":"publisher","DOI":"10.1084\/jem.182.6.1769","article-title":"Immunopathology of Interleukin (IL) 2-Deficient Mice: Thymus Dependence and Suppression by Thymus-Dependent Cells With an Intact IL-2 Gene","volume":"182","author":"Kramer","year":"1995","journal-title":"J Exp Med"},{"key":"B36","doi-asserted-by":"publisher","DOI":"10.1016\/1074-7613(95)90180-9","article-title":"Interleukin-2 Receptor Alpha Chain Regulates the Size and Content of the Peripheral Lymphoid Compartment","volume":"3","author":"Willerford","year":"1995","journal-title":"Immunity"},{"key":"B37","doi-asserted-by":"publisher","DOI":"10.1126\/science.7770771","article-title":"Deregulated T Cell Activation and Autoimmunity in Mice Lacking Interleukin-2 Receptor Beta","volume":"268","author":"Suzuki","year":"1995","journal-title":"Science"},{"key":"B38","doi-asserted-by":"crossref","DOI":"10.4049\/jimmunol.125.6.2555","article-title":"Thymoma Production of T Cell Growth Factor (Interleukin 2)","volume":"125","author":"Farrar","year":"1980","journal-title":"J Immunol"},{"key":"B39","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.93.5.2077","article-title":"Different Interleukin 2 Receptor Beta-Chain Tyrosines Couple to at Least Two Signaling Pathways and Synergistically Mediate Interleukin 2-Induced Proliferation","volume":"93","author":"Friedmann","year":"1996","journal-title":"Proc Natl Acad Sci U.S.A."},{"key":"B40","doi-asserted-by":"publisher","DOI":"10.1126\/science.181845","article-title":"Selective In Vitro Growth of T Lymphocytes From Normal Human Bone Marrows","volume":"193","author":"Morgan","year":"1976","journal-title":"Science"},{"key":"B41","article-title":"X-Linked Lymphoreticular Disease in the Scurfy (Sf) Mutant Mouse","volume":"138","author":"Godfrey","year":"1991","journal-title":"Am J Pathol"},{"key":"B42","doi-asserted-by":"publisher","DOI":"10.1038\/ni1263","article-title":"A Function for Interleukin 2 in Foxp3-Expressing Regulatory T Cells","volume":"6","author":"Fontenot","year":"2005","journal-title":"Nat Immunol"},{"key":"B43","doi-asserted-by":"publisher","DOI":"10.1038\/ni1264","article-title":"Development and Function of Agonist-Induced CD25+Foxp3+ Regulatory T Cells in the Absence of Interleukin 2 Signaling","volume":"6","author":"D\u2019Cruz","year":"2005","journal-title":"Nat Immunol"},{"key":"B44","doi-asserted-by":"publisher","DOI":"10.1084\/jem.20020190","article-title":"Interleukin 2 Signaling Is Required for CD4(+) Regulatory T Cell Function","volume":"196","author":"Furtado","year":"2002","journal-title":"J Exp Med"},{"key":"B45","doi-asserted-by":"publisher","first-page":"5368","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":"B46","doi-asserted-by":"publisher","DOI":"10.1002\/eji.200737101","article-title":"Il-2rbeta Links Il-2r Signaling With Foxp3 Expression","volume":"37","author":"Soper","year":"2007","journal-title":"Eur J Immunol"},{"key":"B47","doi-asserted-by":"publisher","DOI":"10.1016\/j.immuni.2019.03.028","article-title":"The Gammac Family of Cytokines: Basic Biology to Therapeutic Ramifications","volume":"50","author":"Leonard","year":"2019","journal-title":"Immunity"},{"key":"B48","doi-asserted-by":"publisher","DOI":"10.1016\/1074-7613(95)90141-8","article-title":"The Role of Shared Receptor Motifs and Common Stat Proteins in the Generation of Cytokine Pleiotropy and Redundancy by IL-2, IL-4, IL-7, IL-13, and IL-15","volume":"2","author":"Lin","year":"1995","journal-title":"Immunity"},{"key":"B49","doi-asserted-by":"publisher","DOI":"10.4049\/jimmunol.178.1.280","article-title":"IL-2 Receptor Beta-Dependent STAT5 Activation Is Required for the Development of Foxp3+ Regulatory T Cells","volume":"178","author":"Burchill","year":"2007","journal-title":"J Immunol"},{"key":"B50","doi-asserted-by":"publisher","DOI":"10.4049\/jimmunol.181.5.3285","article-title":"IL-2, -7, and -15, But Not Thymic Stromal Lymphopoeitin, Redundantly Govern CD4+Foxp3+ Regulatory T Cell Development","volume":"181","author":"Vang","year":"2008","journal-title":"J Immunol"},{"key":"B51","doi-asserted-by":"publisher","DOI":"10.4049\/jimmunol.181.1.225","article-title":"A Function for IL-7R for CD4+CD25+Foxp3+ T Regulatory Cells","volume":"181","author":"Bayer","year":"2008","journal-title":"J Immunol"},{"key":"B52","doi-asserted-by":"publisher","DOI":"10.1182\/blood-2006-11-055756","article-title":"Nonredundant Roles for Stat5a\/B in Directly Regulating Foxp3","volume":"109","author":"Yao","year":"2007","journal-title":"Blood"},{"key":"B53","doi-asserted-by":"publisher","DOI":"10.4049\/jimmunol.171.11.5853","article-title":"Distinct Effects of STAT5 Activation on CD4+ and CD8+ T Cell Homeostasis: Development of CD4+CD25+ Regulatory T Cells Versus CD8+ Memory T Cells","volume":"171","author":"Burchill","year":"2003","journal-title":"J Immunol"},{"key":"B54","doi-asserted-by":"publisher","first-page":"931","DOI":"10.1016\/j.immuni.2021.03.020","article-title":"A Distal Foxp3 Enhancer Enables Interleukin-2 Dependent Thymic Treg Cell Lineage Commitment for Robust Immune Tolerance","volume":"54","author":"Dikiy","year":"2021","journal-title":"Immunity"},{"key":"B55","doi-asserted-by":"publisher","first-page":"947","DOI":"10.1016\/j.immuni.2021.04.005","article-title":"Distinct Foxp3 Enhancer Elements Coordinate Development, Maintenance, and Function of Regulatory T Cells","volume":"54","author":"Kawakami","year":"2021","journal-title":"Immunity"},{"key":"B56","doi-asserted-by":"publisher","DOI":"10.1038\/ni.1677","article-title":"IL-4 Inhibits TGF-Beta-Induced Foxp3+ T Cells and, Together With TGF-Beta, Generates IL-9+ IL-10+ Foxp3(-) Effector T Cells","volume":"9","author":"Dardalhon","year":"2008","journal-title":"Nat Immunol"},{"key":"B57","doi-asserted-by":"publisher","DOI":"10.1038\/ni.3252","article-title":"The DNA-Binding Inhibitor Id3 Regulates IL-9 Production in CD4(+) T Cells","volume":"16","author":"Nakatsukasa","year":"2015","journal-title":"Nat Immunol"},{"key":"B58","doi-asserted-by":"publisher","DOI":"10.3389\/fimmu.2017.00214","article-title":"Interleukin-4 Inhibits Regulatory T Cell Differentiation Through Regulating Cd103+ Dendritic Cells","volume":"8","author":"Tu","year":"2017","journal-title":"Front Immunol"},{"key":"B59","doi-asserted-by":"publisher","DOI":"10.4049\/jimmunol.1900662","article-title":"Regulatory T Cell Development in the Thymus","volume":"203","author":"Owen","year":"2019","journal-title":"J Immunol"},{"key":"B60","doi-asserted-by":"publisher","DOI":"10.1016\/j.cell.2006.05.042","article-title":"Foxp3 Controls Regulatory T Cell Function Through Cooperation With Nfat","volume":"126","author":"Wu","year":"2006","journal-title":"Cell"},{"key":"B61","doi-asserted-by":"publisher","DOI":"10.1038\/ni0901-882","article-title":"Inducible IL-2 Production by Dendritic Cells Revealed by Global Gene Expression Analysis","volume":"2","author":"Granucci","year":"2001","journal-title":"Nat Immunol"},{"key":"B62","doi-asserted-by":"publisher","DOI":"10.4049\/jimmunol.1800097","article-title":"Identification of Cellular Sources of IL-2 Needed for Regulatory T Cell Development and Homeostasis","volume":"200","author":"Owen","year":"2018","journal-title":"J Immunol"},{"key":"B63","doi-asserted-by":"publisher","DOI":"10.1084\/jem.20190993","article-title":"IL-2 Production by Self-Reactive CD4 Thymocytes Scales Regulatory T Cell Generation in the Thymus","volume":"216","author":"Hemmers","year":"2019","journal-title":"J Exp Med"},{"key":"B64","doi-asserted-by":"publisher","DOI":"10.4049\/jimmunol.1200586","article-title":"Identification of IL-7-Producing Cells in Primary and Secondary Lymphoid Organs Using IL-7-GFP Knock-in Mice","volume":"189","author":"Hara","year":"2012","journal-title":"J Immunol"},{"key":"B65","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.1318281111","article-title":"Characterization of the IL-15 Niche in Primary and Secondary Lymphoid Organs In Vivo","volume":"111","author":"Cui","year":"2014","journal-title":"Proc Natl Acad Sci USA"},{"key":"B66","doi-asserted-by":"publisher","DOI":"10.1038\/nri3667","article-title":"Positive and Negative Selection of the T Cell Repertoire: What Thymocytes See (and Don\u2019t See)","volume":"14","author":"Klein","year":"2014","journal-title":"Nat Rev Immunol"},{"key":"B67","doi-asserted-by":"publisher","DOI":"10.1016\/j.immuni.2013.03.002","article-title":"Development and Maintenance of Regulatory T Cells","volume":"38","author":"Ohkura","year":"2013","journal-title":"Immunity"},{"key":"B68","doi-asserted-by":"publisher","DOI":"10.1038\/ni1444","article-title":"Selection of Foxp3+ Regulatory T Cells Specific for Self Antigen Expressed and Presented by Aire+ Medullary Thymic Epithelial Cells","volume":"8","author":"Aschenbrenner","year":"2007","journal-title":"Nat Immunol"},{"key":"B69","doi-asserted-by":"publisher","DOI":"10.1084\/jem.20122070","article-title":"The Thymic Medulla is Required for Foxp3+ Regulatory But Not Conventional CD4+ Thymocyte Development","volume":"210","author":"Cowan","year":"2013","journal-title":"J Exp Med"},{"key":"B70","doi-asserted-by":"publisher","DOI":"10.1084\/jem.20030152","article-title":"Conversion of Peripheral CD4+CD25- Naive T Cells to CD4+CD25+ Regulatory T Cells by TGF-Beta Induction of Transcription Factor Foxp3","volume":"198","author":"Chen","year":"2003","journal-title":"J Exp Med"},{"key":"B71","doi-asserted-by":"publisher","DOI":"10.1038\/nri.2016.112","article-title":"Immunoregulation by Members of the Tgfbeta Superfamily","volume":"16","author":"Chen","year":"2016","journal-title":"Nat Rev Immunol"},{"key":"B72","doi-asserted-by":"publisher","DOI":"10.1084\/jem.20042276","article-title":"TGF-Beta1 Maintains Suppressor Function and Foxp3 Expression in CD4+CD25+ Regulatory T Cells","volume":"201","author":"Marie","year":"2005","journal-title":"J Exp Med"},{"key":"B73","doi-asserted-by":"publisher","DOI":"10.1016\/j.immuni.2006.07.011","article-title":"Transforming Growth Factor-Beta Controls Development, Homeostasis, and Tolerance of T Cells by Regulatory T Cell-Dependent and -Independent Mechanisms","volume":"25","author":"Li","year":"2006","journal-title":"Immunity"},{"key":"B74","doi-asserted-by":"publisher","DOI":"10.1016\/j.immuni.2006.07.012","article-title":"Cellular Mechanisms of Fatal Early-Onset Autoimmunity in Mice With the T Cell-Specific Targeting of Transforming Growth Factor-Beta Receptor","volume":"25","author":"Marie","year":"2006","journal-title":"Immunity"},{"key":"B75","doi-asserted-by":"publisher","DOI":"10.1038\/nature10772","article-title":"Extrathymically Generated Regulatory T Cells Control Mucosal Th2 Inflammation","volume":"482","author":"Josefowicz","year":"2012","journal-title":"Nature"},{"key":"B76","doi-asserted-by":"publisher","DOI":"10.1038\/nature08750","article-title":"Role of Conserved non-Coding DNA Elements in the Foxp3 Gene in Regulatory T-Cell Fate","volume":"463","author":"Zheng","year":"2010","journal-title":"Nature"},{"key":"B77","doi-asserted-by":"publisher","DOI":"10.1016\/j.immuni.2017.03.015","article-title":"Transforming Growth Factor-Beta Signaling in Regulatory T Cells Controls T Helper-17 Cells and Tissue-Specific Immune Responses","volume":"46","author":"Konkel","year":"2017","journal-title":"Immunity"},{"key":"B78","doi-asserted-by":"publisher","DOI":"10.1016\/j.immuni.2010.04.012","article-title":"Transforming Growth Factor-Beta Signaling Curbs Thymic Negative Selection Promoting Regulatory T Cell Development","volume":"32","author":"Ouyang","year":"2010","journal-title":"Immunity"},{"key":"B79","doi-asserted-by":"publisher","DOI":"10.1084\/jem.194.4.439","article-title":"Requirement for Transforming Growth Factor Beta1 in Controlling T Cell Apoptosis","volume":"194","author":"Chen","year":"2001","journal-title":"J Exp Med"},{"key":"B80","doi-asserted-by":"publisher","first-page":"194","DOI":"10.1038\/ni1549","article-title":"Smad3 and NFAT Cooperate to Induce Foxp3 Expression Through its Enhancer","volume":"9","author":"Tone","year":"2008","journal-title":"Nat Immunol"},{"key":"B81","doi-asserted-by":"publisher","DOI":"10.1016\/j.immuni.2009.10.006","article-title":"Development of Foxp3(+) Regulatory T Cells Is Driven by the C-Rel Enhanceosome","volume":"31","author":"Ruan","year":"2009","journal-title":"Immunity"},{"key":"B82","doi-asserted-by":"publisher","DOI":"10.1084\/jem.20112646","article-title":"Smad3 Binding to the Foxp3 Enhancer is Dispensable for the Development of Regulatory T Cells With the Exception of the Gut","volume":"209","author":"Schlenner","year":"2012","journal-title":"J Exp Med"},{"key":"B83","doi-asserted-by":"publisher","DOI":"10.1038\/372100a0","article-title":"T-Cell Apoptosis Detected in Situ During Positive and Negative Selection in the Thymus","volume":"372","author":"Surh","year":"1994","journal-title":"Nature"},{"key":"B84","doi-asserted-by":"publisher","DOI":"10.1084\/jem.20050784","article-title":"Developmental Regulation of Foxp3 Expression During Ontogeny","volume":"202","author":"Fontenot","year":"2005","journal-title":"J Exp Med"},{"key":"B85","doi-asserted-by":"publisher","DOI":"10.1016\/s1074-7613(01)00147-9","article-title":"TGF-Beta Released by Apoptotic T Cells Contributes to an Immunosuppressive Milieu","volume":"14","author":"Chen","year":"2001","journal-title":"Immunity"},{"key":"B86","doi-asserted-by":"publisher","DOI":"10.1038\/nm1749","article-title":"Cd3-Specific Antibody-Induced Immune Tolerance Involves Transforming Growth Factor-Beta From Phagocytes Digesting Apoptotic T Cells","volume":"14","author":"Perruche","year":"2008","journal-title":"Nat Med"},{"key":"B87","doi-asserted-by":"publisher","DOI":"10.1172\/JCI1112","article-title":"Macrophages That Have Ingested Apoptotic Cells In Vitro Inhibit Proinflammatory Cytokine Production Through Autocrine\/Paracrine Mechanisms Involving TGF-Beta, PGE2, and PAF","volume":"101","author":"Fadok","year":"1998","journal-title":"J Clin Invest"},{"key":"B88","doi-asserted-by":"publisher","first-page":"51","DOI":"10.1146\/annurev-immunol-032713-120257","article-title":"TGF-Beta Activation and Function in Immunity","volume":"32","author":"Travis","year":"2014","journal-title":"Annu Rev Immunol"},{"key":"B89","doi-asserted-by":"publisher","DOI":"10.1038\/nature10152","article-title":"Latent TGF-Beta Structure and Activation","volume":"474","author":"Shi","year":"2011","journal-title":"Nature"},{"key":"B90","doi-asserted-by":"publisher","DOI":"10.1210\/mend.10.9.8885242","article-title":"Redox-Mediated Activation of Latent Transforming Growth Factor-Beta 1","volume":"10","author":"Barcellos-Hoff","year":"1996","journal-title":"Mol Endocrinol"},{"key":"B91","doi-asserted-by":"publisher","first-page":"671","DOI":"10.1016\/j.immuni.2019.08.001","article-title":"High Glucose Intake Exacerbates Autoimmunity Through Reactive-Oxygen-Species-Mediated Tgf-Beta Cytokine Activation","volume":"51","author":"Zhang","year":"2019","journal-title":"Immunity"},{"key":"B92","doi-asserted-by":"publisher","DOI":"10.1038\/nm.4375","article-title":"D-Mannose Induces Regulatory T Cells and Suppresses Immunopathology","volume":"23","author":"Zhang","year":"2017","journal-title":"Nat Med"},{"key":"B93","doi-asserted-by":"publisher","DOI":"10.1007\/s00281-016-0612-y","article-title":"TNF Superfamily Cytokines in the Promotion of Th9 Differentiation and Immunopathology","volume":"39","author":"Meylan","year":"2017","journal-title":"Semin Immunopathol"},{"key":"B94","doi-asserted-by":"publisher","DOI":"10.1038\/nri2526","article-title":"The Role of TNF Superfamily Members in T-Cell Function and Diseases","volume":"9","author":"Croft","year":"2009","journal-title":"Nat Rev Immunol"},{"key":"B95","doi-asserted-by":"publisher","DOI":"10.4049\/jimmunol.0900010","article-title":"Thymic OX40 Expression Discriminates Cells Undergoing Strong Responses to Selection Ligands","volume":"182","author":"Klinger","year":"2009","journal-title":"J Immunol"},{"key":"B96","doi-asserted-by":"publisher","DOI":"10.1172\/JCI42945","article-title":"Pathogenic T Cells Have a Paradoxical Protective Effect in Murine Autoimmune Diabetes by Boosting Tregs","volume":"120","author":"Grinberg-Bleyer","year":"2010","journal-title":"J Clin Invest"},{"key":"B97","doi-asserted-by":"publisher","DOI":"10.1093\/carcin\/bgt038","article-title":"Tumor Necrosis Factor Receptor 2-Dependent Homeostasis of Regulatory T Cells as a Player in TNF-Induced Experimental Metastasis","volume":"34","author":"Chopra","year":"2013","journal-title":"Carcinogenesis"},{"key":"B98","doi-asserted-by":"publisher","DOI":"10.4049\/jimmunol.179.1.154","article-title":"Interaction of TNF With TNF Receptor Type 2 Promotes Expansion and Function of Mouse CD4+CD25+ T Regulatory Cells","volume":"179","author":"Chen","year":"2007","journal-title":"J Immunol"},{"key":"B99","doi-asserted-by":"publisher","DOI":"10.4049\/jimmunol.1202659","article-title":"TNFR2 Is Critical for the Stabilization of the CD4+Foxp3+ Regulatory T. Cell Phenotype in the Inflammatory Environment","volume":"190","author":"Chen","year":"2013","journal-title":"J Immunol"}],"container-title":["Frontiers in Immunology"],"original-title":[],"link":[{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fimmu.2022.883560\/full","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2023,1,30]],"date-time":"2023-01-30T21:42:33Z","timestamp":1675114953000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fimmu.2022.883560\/full"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2022,3,31]]},"references-count":99,"alternative-id":["10.3389\/fimmu.2022.883560"],"URL":"https:\/\/doi.org\/10.3389\/fimmu.2022.883560","relation":{},"ISSN":["1664-3224"],"issn-type":[{"value":"1664-3224","type":"electronic"}],"subject":[],"published":{"date-parts":[[2022,3,31]]},"article-number":"883560"}}