{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,12]],"date-time":"2026-09-12T09:39:43Z","timestamp":1789205983639,"version":"build-2803163510"},"reference-count":80,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2026,7,8]],"date-time":"2026-07-08T00:00:00Z","timestamp":1783468800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100007061","name":"Secretar\u00eda Nacional de Ciencia, Tecnolog\u00eda e Innovaci\u00f3n","doi-asserted-by":"publisher","id":[{"id":"10.13039\/501100007061","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100010567","name":"Secretar\u00eda de Estado de Ciencia, Tecnolog\u00eda e Innovaci\u00f3n","doi-asserted-by":"publisher","id":[{"id":"10.13039\/501100010567","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Immunol."],"abstract":"<jats:sec>\n                    <jats:title>Introduction<\/jats:title>\n                    <jats:p>\n                      While numerous preclinical models emphasize the therapeutic promise of\n                      <jats:italic>in vitro<\/jats:italic>\n                      -induced Tregs (iTregs) for managing inflammatory diseases and promoting tolerance, their translation to clinical use is limited by concerns over phenotypic and functional instability, largely due to an epigenetic profile distinct from thymic Tregs.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>To address this, we generated and expanded iTregs in the presence of Vitamin C, known to activate TET enzymes that demethylate critical gene regions such as FOXP3. Antigen-specific Tregs were derived from allogeneic co-cultures of monocyte-derived dendritic cells and na\u00efve T cells. After 7 days, allo-Tregs were isolated by FACS and further expanded for 3 weeks with IL-2, TGF-\u03b2, rapamycin, with or without Vitamin C supplementation.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>\n                      iTregs treated with Vitamin C displayed heightened FOXP3 expression and sustained high levels of suppressive markers (PD-L1, CD39, TIGIT, and CTLA-4), as well as chemokine receptors linked to allograft homing (CCR4, CCR5, and CXCR3). These cells also demonstrated enhanced allospecific suppression of CD4\n                      <jats:sup>+<\/jats:sup>\n                      and CD8\n                      <jats:sup>+<\/jats:sup>\n                      T cell proliferation, even in the presence of pro-inflammatory cytokines. Notably, this proinflammatory milieu did not trigger the production of intracellular cytokines IL-17 and IFN-\u03b3 by allo-iTregs, confirming their sustained phenotypic and functional stability. Advanced analysis demonstrated that allo-iTregs possess a unique profile, setting them apart from conventional T cells. Pyrosequencing of the FOXP3 TSDR revealed reduced CpG methylation in Vitamin C-treated iTregs (60.9% at day 21 and 43.5% at day 28) compared to untreated allo-iTregs (85.9% at day 21 and 80.5% at day 28) and na\u00efve T cells (92.8%). In addition, transcriptomic analysis demonstrated that the core Treg transcriptional signature remained largely intact with Vitamin C treatment, irrespective of cytokine exposure, whereas the major transcriptional changes were associated with activation, proliferation, and cell cycle regulation.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Discussion<\/jats:title>\n                    <jats:p>In summary, Vitamin C enhances both the phenotypic and functional stability of allospecific iTregs, even under proinflammatory conditions, correlating with increased TSDR demethylation, while preserving the transcription of key Treg genes. These results suggest that Vitamin C-treated allospecific iTregs are superior candidates for immunotherapy strategies to promote long-term tolerance in transplant recipients.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.3389\/fimmu.2026.1827886","type":"journal-article","created":{"date-parts":[[2026,7,8]],"date-time":"2026-07-08T05:53:28Z","timestamp":1783490008000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":1,"title":["Increased phenotypic and functional stability of human allospecific induced Tregs is associated with Vitamin C-mediated FOXP3 TSDR demethylation"],"prefix":"10.3389","volume":"17","author":[{"given":"Evelyn K.","family":"Alvarez-Salazar","sequence":"first","affiliation":[{"name":"Department of Immunology, Biomedical Research Institute, National Autonomous University of Mexico","place":["Mexico City, Mexico"]},{"name":"National Laboratory of Flow Cytometry, Biomedical Research Institute, National Autonomous University of Mexico","place":["Mexico City, Mexico"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Judith E.","family":"Reyes-Barrientos","sequence":"additional","affiliation":[{"name":"Department of Immunology, Biomedical Research Institute, National Autonomous University of Mexico","place":["Mexico City, Mexico"]},{"name":"National Laboratory of Flow Cytometry, Biomedical Research Institute, National Autonomous University of Mexico","place":["Mexico City, Mexico"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Arimelek","family":"Cort\u00e9s-Hern\u00e1ndez","sequence":"additional","affiliation":[{"name":"Department of Immunology, Biomedical Research Institute, National Autonomous University of Mexico","place":["Mexico City, Mexico"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Abril","family":"Saint-Martin Castellanos","sequence":"additional","affiliation":[{"name":"Department of Immunology, Biomedical Research Institute, National Autonomous University of Mexico","place":["Mexico City, Mexico"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sa\u00fal","family":"Arteaga-Cruz","sequence":"additional","affiliation":[{"name":"Department of Immunology, Biomedical Research Institute, National Autonomous University of Mexico","place":["Mexico City, Mexico"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alejandra","family":"Cervera","sequence":"additional","affiliation":[{"name":"Biomedical Genomics and Bioinformatics Laboratory, Instituto Nacional de Medicina Gen\u00f3mica","place":["Mexico City, Mexico"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Iyari","family":"Mart\u00ednez-Iturbe","sequence":"additional","affiliation":[{"name":"Department of Immunology, Biomedical Research Institute, National Autonomous University of Mexico","place":["Mexico City, Mexico"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Beatriz E.","family":"S\u00e1nchez-Hern\u00e1ndez","sequence":"additional","affiliation":[{"name":"Department of Pathology, Instituto Nacional de Ciencias M\u00e9dicas y Nutrici\u00f3n Salvador Zubir\u00e1n","place":["Mexico City, Mexico"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Armando","family":"Gamboa-Dom\u00ednguez","sequence":"additional","affiliation":[{"name":"Department of Pathology, Instituto Nacional de Ciencias M\u00e9dicas y Nutrici\u00f3n Salvador Zubir\u00e1n","place":["Mexico City, Mexico"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Gloria","family":"Soldevila","sequence":"additional","affiliation":[{"name":"Department of Immunology, Biomedical Research Institute, National Autonomous University of Mexico","place":["Mexico City, Mexico"]},{"name":"National Laboratory of Flow Cytometry, Biomedical Research Institute, National Autonomous University of Mexico","place":["Mexico City, Mexico"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2026,7,8]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","DOI":"10.3390\/jcm14103602","article-title":"Complications associated with immunosuppressive agents in solid organ transplant recipients: A nationwide analysis","volume":"14","author":"Lee","year":"2025","journal-title":"J Clin Med"},{"key":"B2","doi-asserted-by":"publisher","DOI":"10.3389\/ti.2025.14958","article-title":"Tolerance induction strategies in organ transplantation: Current status and future perspectives","volume":"38","author":"Blein","year":"2025","journal-title":"Transpl Int"},{"key":"B3","doi-asserted-by":"publisher","DOI":"10.1038\/s41581-023-00733-w","article-title":"Regulatory T cells in autoimmune kidney diseases and transplantation","volume":"19","author":"Mikami","year":"2023","journal-title":"Nat Rev Nephrol"},{"key":"B4","doi-asserted-by":"publisher","first-page":"6","DOI":"10.1016\/j.cell.2025.11.035","article-title":"Next steps in regulatory T cells: Biology and clinical application","volume":"189","author":"Zou","year":"2026","journal-title":"Cell"},{"key":"B5","doi-asserted-by":"publisher","DOI":"10.1146\/annurev-immunol-042718-041717","article-title":"Regulatory T cells and human disease","volume":"38","author":"Sakaguchi","year":"2020","journal-title":"Annu Rev Immunol"},{"key":"B6","doi-asserted-by":"publisher","first-page":"1","DOI":"10.1007\/978-981-15-6407-9_1","article-title":"Regulatory T cells: Concept, classification, phenotype, and biological characteristics","volume":"1278","author":"Du","year":"2021","journal-title":"Adv Exp Med Biol"},{"key":"B7","doi-asserted-by":"publisher","DOI":"10.1016\/j.it.2016.08.012","article-title":"Induced regulatory T cells: Their development, stability, and applications","volume":"37","author":"Kanamori","year":"2016","journal-title":"Trends Immunol"},{"key":"B8","doi-asserted-by":"publisher","DOI":"10.1093\/jleuko\/qiae062","article-title":"Induced regulatory T cells as immunotherapy in allotransplantation and autoimmunity: Challenges and opportunities","volume":"116","author":"Alvarez-Salazar","year":"2024","journal-title":"J Leukoc Biol"},{"key":"B9","doi-asserted-by":"publisher","DOI":"10.1126\/scitranslmed.adq9913","article-title":"Conversion of pathogenic T cells into functionally stabilized Treg cells for antigen-specific immunosuppression in pemphigus vulgaris","volume":"17","author":"Mukai","year":"2025","journal-title":"Sci Transl Med"},{"key":"B10","doi-asserted-by":"publisher","DOI":"10.4049\/jimmunol.1003947","article-title":"Foxp3+-inducible regulatory T cells suppress endothelial activation and leukocyte recruitment","volume":"187","author":"Maganto-Garc\u00eda","year":"2011","journal-title":"J Immunol"},{"key":"B11","doi-asserted-by":"publisher","DOI":"10.4049\/jimmunol.180.11.7112","article-title":"Cutting edge: Foxp3+CD4+CD25+ regulatory T cells induced by IL-2 and TGF-beta are resistant to Th17 conversion by IL-6","volume":"180","author":"Zheng","year":"2008","journal-title":"J Immunol"},{"key":"B12","doi-asserted-by":"publisher","first-page":"1869","DOI":"10.1016\/j.celrep.2019.01.066","article-title":"Negligible effect of sodium chloride on the development and function of TGF-\u03b2-induced CD4+ Foxp3+ regulatory T cells","volume":"26","author":"Luo","year":"2019","journal-title":"Cell Rep"},{"key":"B13","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0104698","article-title":"In vitro induced regulatory T cells are unique from endogenous regulatory T cells and effective at suppressing late stages of ongoing autoimmunity","volume":"9","author":"Nguyen","year":"2014","journal-title":"PloS One"},{"key":"B14","doi-asserted-by":"publisher","DOI":"10.3389\/fimmu.2025.1636434","article-title":"Differential regulation of Treg stability in human na\u00efve and effector Treg subsets by TGF\u03b2-signaling via ARKADIA-SKI axis","volume":"16","author":"Yang","year":"2025","journal-title":"Front Immunol"},{"key":"B15","doi-asserted-by":"publisher","DOI":"10.3389\/fimmu.2025.1709915","article-title":"The immunobiology and therapeutic potential of regulatory T cells in autoimmune diseases and allergic diseases","volume":"16","author":"Xie","year":"2026","journal-title":"Front Immunol"},{"key":"B16","doi-asserted-by":"publisher","DOI":"10.4049\/jimmunol.1203473","article-title":"Active demethylation of the Foxp3 locus leads to the generation of stable regulatory T cells within the thymus","volume":"190","author":"Toker","year":"2013","journal-title":"J Immunol"},{"key":"B17","doi-asserted-by":"publisher","DOI":"10.1038\/ni.3646","article-title":"Guidance of regulatory T cell development by Satb1-dependent super-enhancer establishment","volume":"18","author":"Kitagawa","year":"2017","journal-title":"Nat Immunol"},{"key":"B18","doi-asserted-by":"publisher","DOI":"10.1007\/s00109-010-0642-1","article-title":"Methylation matters: Binding of Ets-1 to the demethylated Foxp3 gene contributes to the stabilization of Foxp3 expression in regulatory T cells","volume":"88","author":"Polansky","year":"2010","journal-title":"J Mol Med"},{"key":"B19","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0182009","article-title":"Single and combined effect of retinoic acid and rapamycin modulate the generation, activity and homing potential of induced human regulatory T cells","volume":"12","author":"Candia","year":"2017","journal-title":"PloS One"},{"key":"B20","doi-asserted-by":"publisher","first-page":"4077","DOI":"10.1038\/s41467-021-24331-1","article-title":"Microbial short-chain fatty acids modulate CD8+ T cell responses and improve adoptive immunotherapy for cancer","volume":"12","author":"Luu","year":"2021","journal-title":"Nat Commun"},{"key":"B21","doi-asserted-by":"publisher","DOI":"10.1084\/jem.20151438","article-title":"Control of Foxp3 stability through modulation of TET activity","volume":"213","author":"Yue","year":"2016","journal-title":"J Exp Med"},{"key":"B22","doi-asserted-by":"publisher","DOI":"10.1126\/sciimmunol.aaw2707","article-title":"Conversion of antigen-specific effector\/memory T cells into Foxp3-expressing Treg cells by inhibition of CDK8\/19","volume":"4","author":"Akamatsu","year":"2019","journal-title":"Sci Immunol"},{"key":"B23","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.1922600117","article-title":"Epigenetic conversion of conventional T cells into regulatory T cells by CD28 signal deprivation","volume":"117","author":"Mikami","year":"2020","journal-title":"Proc Natl Acad Sci USA"},{"key":"B24","doi-asserted-by":"publisher","first-page":"24","DOI":"10.1186\/s13072-017-0129-1","article-title":"Stabilization of Foxp3 expression by CRISPR-dCas9-based epigenome editing in mouse primary T cells","volume":"10","author":"Okada","year":"2017","journal-title":"Epigenet Chromatin"},{"key":"B25","doi-asserted-by":"publisher","DOI":"10.3389\/fimmu.2020.609891","article-title":"Targeted de-methylation of the FOXP3-TSDR is sufficient to induce physiological FOXP3 expression but not a functional Treg phenotype","volume":"11","author":"Kressler","year":"2021","journal-title":"Front Immunol"},{"key":"B26","doi-asserted-by":"publisher","DOI":"10.4049\/jimmunol.1502352","article-title":"Vitamin C facilitates demethylation of the Foxp3 enhancer in a Tet-dependent manner","volume":"196","author":"Sasidharan Nair","year":"2016","journal-title":"J Immunol"},{"key":"B27","doi-asserted-by":"publisher","DOI":"10.1093\/intimm\/dxx049","article-title":"Improvement of Foxp3 stability through CNS2 demethylation by TET enzyme induction and activation","volume":"29","author":"Someya","year":"2017","journal-title":"Int Immunol"},{"key":"B28","doi-asserted-by":"publisher","DOI":"10.3389\/fimmu.2017.00748","article-title":"Alloantigen-induced regulatory T cells generated in presence of vitamin C display enhanced stability of Foxp3 expression and promote skin allograft acceptance","volume":"8","author":"Nikolouli","year":"2017","journal-title":"Front Immunol"},{"key":"B29","doi-asserted-by":"publisher","DOI":"10.3389\/fimmu.2020.00375","article-title":"Large-scale generation of human allospecific induced Tregs with functional stability for use in immunotherapy in transplantation","volume":"11","author":"Alvarez-Salazar","year":"2020","journal-title":"Front Immunol"},{"key":"B30","doi-asserted-by":"publisher","DOI":"10.3389\/fcell.2021.751590","article-title":"Strong expansion of human regulatory T cells for adoptive cell therapy results in epigenetic changes which may impact their survival and function","volume":"9","author":"Ou","year":"2021","journal-title":"Front Cell Dev Biol"},{"key":"B31","doi-asserted-by":"publisher","DOI":"10.1093\/bioinformatics\/bty560","article-title":"fastp: An ultra-fast all-in-one FASTQ preprocessor","volume":"34","author":"Chen","year":"2018","journal-title":"Bioinformatics"},{"key":"B32","doi-asserted-by":"publisher","DOI":"10.1038\/nmeth.4197","article-title":"Salmon provides fast and bias-aware quantification of transcript expression","volume":"14","author":"Patro","year":"2017","journal-title":"Nat Methods"},{"key":"B33","doi-asserted-by":"publisher","first-page":"1521","DOI":"10.12688\/f1000research.7563.2","article-title":"Differential analyses for RNA-seq: Transcript-level estimates improve gene-level inferences","volume":"4","author":"Soneson","year":"2015","journal-title":"F1000Res"},{"key":"B34","doi-asserted-by":"publisher","DOI":"10.1186\/s13059-014-0550-8","article-title":"Moderated estimation of fold change and dispersion for RNA-seq data with DESeq2","volume":"15","author":"Love","year":"2014","journal-title":"Genome Biol"},{"key":"B35","doi-asserted-by":"publisher","DOI":"10.1038\/jid.2015.287","article-title":"Integrin \u03b1E(CD103) is involved in regulatory T-cell function in allergic contact hypersensitivity","volume":"135","author":"Braun","year":"2015","journal-title":"J Invest Dermatol"},{"key":"B36","doi-asserted-by":"publisher","DOI":"10.1172\/jci.insight.124427","article-title":"TIGIT signaling restores suppressor function of Th1 Tregs","volume":"4","author":"Lucca","year":"2019","journal-title":"JCI Insight"},{"key":"B37","doi-asserted-by":"publisher","DOI":"10.1038\/nature06878","article-title":"TGF-beta-induced Foxp3 inhibits T(H)17 cell differentiation by antagonizing RORgammat function","volume":"453","author":"Zhou","year":"2008","journal-title":"Nature"},{"key":"B38","doi-asserted-by":"publisher","DOI":"10.1084\/jem.20062512","article-title":"Adenosine generation catalyzed by CD39 and CD73 expressed on regulatory T cells mediates immune suppression","volume":"204","author":"Deaglio","year":"2007","journal-title":"J Exp Med"},{"key":"B39","doi-asserted-by":"publisher","first-page":"2011","DOI":"10.1038\/s41467-019-09541-y","article-title":"Loss of TET2 and TET3 in regulatory T cells unleashes effector function","volume":"10","author":"Yue","year":"2019","journal-title":"Nat Commun"},{"key":"B40","doi-asserted-by":"publisher","DOI":"10.1111\/ajt.15845","article-title":"Epigenetically modifying the Foxp3 locus for generation of stable antigen-specific Tregs as cellular therapeutics","volume":"20","author":"Chen","year":"2020","journal-title":"Am J Transplant"},{"key":"B41","doi-asserted-by":"publisher","DOI":"10.1182\/blood.V130.Suppl_1.70.70","article-title":"Vitamin C stabilizes Foxp3 expression in induced Treg cells by targeted DNA demethylation and prevents murine model of acute graft versus host disease","volume":"130","author":"Kasahara","year":"2017","journal-title":"Blood"},{"key":"B42","doi-asserted-by":"publisher","first-page":"393","DOI":"10.1038\/nbt.3525","article-title":"Quality cell therapy manufacturing by design","volume":"34","author":"Lipsitz","year":"2016","journal-title":"Nat Biotechnol"},{"key":"B43","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.2219086120","article-title":"Tonic-signaling chimeric antigen receptors drive human regulatory T cell exhaustion","volume":"120","author":"Lamarche","year":"2023","journal-title":"Proc Natl Acad Sci USA"},{"key":"B44","doi-asserted-by":"publisher","DOI":"10.3389\/fbioe.2022.886637","article-title":"Influence of culture conditions on ex vivo expansion of T lymphocytes and their function for therapy: Current insights and open questions","volume":"10","author":"Sudarsanam","year":"2022","journal-title":"Front Bioeng Biotechnol"},{"key":"B45","doi-asserted-by":"publisher","first-page":"349","DOI":"10.1097\/MOT.0b013e328355a992","article-title":"Regulatory T-cell therapy for transplantation: How many cells do we need","volume":"17","author":"Tang","year":"2012","journal-title":"Curr Opin Organ Transplant"},{"key":"B46","doi-asserted-by":"publisher","DOI":"10.1002\/eji.200838105","article-title":"DNA methylation controls Foxp3 gene expression","volume":"38","author":"Polansky","year":"2008","journal-title":"Eur J Immunol"},{"key":"B47","doi-asserted-by":"publisher","DOI":"10.1111\/j.1600-6143.2011.03558.x","article-title":"Generation and large-scale expansion of human inducible regulatory T cells that suppress graft-versus-host disease","volume":"11","author":"Hippen","year":"2011","journal-title":"Am J Transplant"},{"key":"B48","doi-asserted-by":"publisher","DOI":"10.3389\/fimmu.2024.1387975","article-title":"Regulation of Treg cells by cytokine signaling and co-stimulatory molecules","volume":"15","author":"Zong","year":"2024","journal-title":"Front Immunol"},{"key":"B49","doi-asserted-by":"publisher","DOI":"10.3389\/fimmu.2021.667834","article-title":"The impact of inflammation on the immune responses to transplantation: Tolerance or rejection","volume":"12","author":"Ravindranath","year":"2021","journal-title":"Front Immunol"},{"key":"B50","doi-asserted-by":"publisher","DOI":"10.1016\/0969-8051(94)90076-0","article-title":"Cytokines and organ transplantation. A review","volume":"21","author":"Pirenne","year":"1994","journal-title":"Nucl Med Biol"},{"key":"B51","doi-asserted-by":"publisher","DOI":"10.1182\/blood-2005-11-4567","article-title":"TNF downmodulates the function of human CD4+CD25hi T-regulatory cells","volume":"108","author":"Valencia","year":"2006","journal-title":"Blood"},{"key":"B52","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.1421463112","article-title":"Inflammation negatively regulates FOXP3 and regulatory T-cell function via DBC1","volume":"112","author":"Gao","year":"2015","journal-title":"Proc Natl Acad Sci"},{"key":"B53","doi-asserted-by":"publisher","first-page":"465","DOI":"10.1038\/s41598-017-00508-x","article-title":"IL-1\u03b2 induced HIF-1\u03b1 inhibits the differentiation of human FOXP3+ T cells","volume":"7","author":"Feldhoff","year":"2017","journal-title":"Sci Rep"},{"key":"B54","doi-asserted-by":"publisher","first-page":"44","DOI":"10.1016\/j.immuni.2008.05.007","article-title":"Molecular antagonism and plasticity of regulatory and inflammatory T cell programs","volume":"29","author":"Yang","year":"2008","journal-title":"Immunity"},{"key":"B55","doi-asserted-by":"publisher","DOI":"10.1126\/science.1160062","article-title":"CTLA-4 control over Foxp3+ regulatory T cell function","volume":"322","author":"Wing","year":"2008","journal-title":"Science"},{"key":"B56","doi-asserted-by":"publisher","DOI":"10.3389\/fimmu.2014.00064","article-title":"The role of ectonucleotidases CD39 and CD73 and adenosine signaling in solid organ transplantation","volume":"5","author":"Roberts","year":"2014","journal-title":"Front Immunol"},{"key":"B57","doi-asserted-by":"publisher","DOI":"10.1016\/j.immuni.2014.02.012","article-title":"Treg cells expressing the coinhibitory molecule TIGIT selectively inhibit proinflammatory Th1 and Th17 cell responses","volume":"40","author":"Joller","year":"2014","journal-title":"Immunity"},{"key":"B58","doi-asserted-by":"publisher","DOI":"10.1016\/j.ajt.2022.12.011","article-title":"TIGIT agonism alleviates costimulation blockade resistant rejection in a Treg-dependent manner","volume":"23","author":"Hartigan","year":"2023","journal-title":"Am J Transplant"},{"key":"B59","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0058006","article-title":"Tim-3 expression defines regulatory T cells in human tumors","volume":"8","author":"Yan","year":"2013","journal-title":"PloS One"},{"key":"B60","doi-asserted-by":"publisher","DOI":"10.4049\/jimmunol.2400119","article-title":"Tim-3 is required for regulatory T cell-mediated promotion of T cell exhaustion and viral persistence during chronic lymphocytic choriomeningitis virus infection","volume":"213","author":"Nieves-Rosado","year":"2024","journal-title":"J Immunol"},{"key":"B61","doi-asserted-by":"publisher","DOI":"10.1016\/j.celrep.2021.109699","article-title":"Expression of Tim-3 drives phenotypic and functional changes in Treg cells in secondary lymphoid organs and the tumor microenvironment","volume":"36","author":"Banerjee","year":"2021","journal-title":"Cell Rep"},{"key":"B62","doi-asserted-by":"publisher","first-page":"316","DOI":"10.12688\/f1000research.13446.1","article-title":"Immune regulation by tim-3","volume":"7","author":"Banerjee","year":"2018","journal-title":"F1000Res"},{"key":"B63","doi-asserted-by":"publisher","DOI":"10.4049\/jimmunol.1400557","article-title":"Too much of a good thing? Tim-3 and TCR signaling in T cell exhaustion","volume":"193","author":"Ferris","year":"2014","journal-title":"J Immunol"},{"key":"B64","doi-asserted-by":"publisher","first-page":"106","DOI":"10.1097\/MOT.0000000000000483","article-title":"Guiding regulatory T cells to the allograft","volume":"23","author":"Lamarche","year":"2018","journal-title":"Curr Opin Organ Transplant"},{"key":"B65","doi-asserted-by":"publisher","DOI":"10.1016\/j.immuni.2008.12.022","article-title":"Regulatory T cells sequentially migrate from inflamed tissues to draining lymph nodes to suppress the alloimmune response","volume":"30","author":"Zhang","year":"2009","journal-title":"Immunity"},{"key":"B66","doi-asserted-by":"publisher","DOI":"10.1084\/jem.20041709","article-title":"Recruitment of Foxp3+ T regulatory cells mediating allograft tolerance depends on the CCR4 chemokine receptor","volume":"201","author":"Lee","year":"2005","journal-title":"J Exp Med"},{"key":"B67","doi-asserted-by":"publisher","DOI":"10.1111\/j.1365-3083.2012.02732.x","article-title":"Peripherally circulating CD4+ FOXP3+ CXCR3+ T regulatory cells correlate with renal allograft function","volume":"76","author":"Hoerning","year":"2012","journal-title":"Scand J Immunol"},{"key":"B68","doi-asserted-by":"publisher","first-page":"33","DOI":"10.1093\/jleuko\/qiae049","article-title":"Stability and plasticity of regulatory T cells in health and disease","volume":"116","author":"Contreras-Castillo","year":"2024","journal-title":"J Leukoc Biol"},{"key":"B69","doi-asserted-by":"publisher","DOI":"10.1155\/2016\/6309219","article-title":"Balancing inflammation: The link between Th17 and regulatory T cells","volume":"2016","author":"Diller","year":"2016","journal-title":"Mediators Inflammation"},{"key":"B70","doi-asserted-by":"publisher","DOI":"10.4049\/jimmunol.1200413","article-title":"IFN-\u03b3 production by allogeneic Foxp3+ regulatory T cells is essential for preventing experimental graft-versus-host disease","volume":"189","author":"Koenecke","year":"2012","journal-title":"J Immunol"},{"key":"B71","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.2401692121","article-title":"IFN-\u03b3-induced Th1-Treg polarization in inflamed brains limits exacerbation of experimental autoimmune encephalomyelitis","volume":"121","author":"Okamoto","year":"2024","journal-title":"Proc Natl Acad Sci USA"},{"key":"B72","doi-asserted-by":"publisher","first-page":"49","DOI":"10.5483\/BMBRep.2017.50.1.193","article-title":"Vitamin C enhances the expression of IL17 in a Jmjd2\u2013dependent manner","volume":"50","author":"Song","year":"2017","journal-title":"BMB Rep"},{"key":"B73","doi-asserted-by":"publisher","DOI":"10.1016\/j.intimp.2007.08.027","article-title":"Rapamycin inhibits differentiation of Th17 cells and promotes generation of FoxP3+ T regulatory cells","volume":"7","author":"Kopf","year":"2007","journal-title":"Int Immunopharmacol"},{"key":"B74","doi-asserted-by":"publisher","DOI":"10.1038\/s41573-019-0041-4","article-title":"Next-generation regulatory T cell therapy","volume":"18","author":"Ferreira","year":"2019","journal-title":"Nat Rev Drug Discov"},{"key":"B75","doi-asserted-by":"publisher","first-page":"6550","DOI":"10.1038\/s41598-020-63572-w","article-title":"Vitamin C supports conversion of human \u03b3\u03b4 T cells into FOXP3-expressing regulatory cells by epigenetic regulation","volume":"10","author":"Kouakanou","year":"2020","journal-title":"Sci Rep"},{"key":"B76","doi-asserted-by":"publisher","DOI":"10.3389\/fimmu.2024.1444533","article-title":"Epigenetic regulation of human FOXP3+ Tregs: From homeostasis maintenance to pathogen defense","volume":"15","author":"Yue","year":"2024","journal-title":"Front Immunol"},{"key":"B77","doi-asserted-by":"publisher","DOI":"10.1038\/ng.2807","article-title":"Vitamin C modulates TET1 function during somatic cell reprogramming","volume":"45","author":"Chen","year":"2013","journal-title":"Nat Genet"},{"key":"B78","doi-asserted-by":"publisher","DOI":"10.4049\/jimmunol.210.Supp.76.24","article-title":"DNA demethylation fine-tunes IL-2 production during thymic development and promotes regulatory T cell differentiation","volume":"210","author":"Issuree","year":"2023","journal-title":"J Immunol"},{"key":"B79","doi-asserted-by":"publisher","first-page":"76","DOI":"10.1186\/s13072-025-00634-1","article-title":"Loss of TET2 activity limits the ability of vitamin C to activate DNA demethylation in human HAP1 cells","volume":"18","author":"Gawronski","year":"2025","journal-title":"Epigenet Chromatin"},{"key":"B80","doi-asserted-by":"publisher","DOI":"10.1093\/intimm\/dxx060","article-title":"Generation of allo-antigen-specific induced Treg stabilized by vitamin C treatment and its application for prevention of acute graft versus host disease model","volume":"29","author":"Kasahara","year":"2017","journal-title":"Int Immunol"}],"container-title":["Frontiers in Immunology"],"original-title":[],"link":[{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fimmu.2026.1827886\/full","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,7,8]],"date-time":"2026-07-08T05:53:30Z","timestamp":1783490010000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fimmu.2026.1827886\/full"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,7,8]]},"references-count":80,"alternative-id":["10.3389\/fimmu.2026.1827886"],"URL":"https:\/\/doi.org\/10.3389\/fimmu.2026.1827886","relation":{},"ISSN":["1664-3224"],"issn-type":[{"value":"1664-3224","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,7,8]]},"article-number":"1827886"}}