{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,25]],"date-time":"2026-09-25T02:10:22Z","timestamp":1790302222433,"version":"4.1.0"},"reference-count":49,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2021,12,7]],"date-time":"2021-12-07T00:00:00Z","timestamp":1638835200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Immunol."],"abstract":"<jats:p>We investigated the characteristics of regulatory T cells (Tregs), focusing on the relationship between their stability and reactive oxygen species (ROS), in antineutrophil cytoplasmic antibody-associated vasculitis (AAV). Intracellular expressions of effector cytokines, forkhead box protein 3 (FoxP3), ROS, phosphorylated mammalian target of rapamycin (mTOR), and sirtuin 1 (SIRT1) in Tregs from peripheral blood mononuclear cells (PBMCs) of patients with AAV and healthy controls (HC) were analyzed. The alterations in and functional ability of Tregs were compared before and after resveratrol (RVL) treatment of PBMCs in patients with AAV. Significantly higher expressions of interferon (IFN)-\u03b3, interleukin (IL)-17, IL-4, ROS, and phosphorylated mTOR (pho-mTOR) and lower expression of SIRT1 in CD4+CD25+FoxP3+ cells were found in patients with AAV than in the HC. FoxP3 expression in CD4+CD25+ cells and suppressive function of Tregs were significantly lower in patients with AAV than in the HC. Tregs after RVL treatment demonstrated significant decreases in IFN-\u03b3, ROS, and pho-mTOR levels and increases in FoxP3, SIRT1 levels, and functional activity. Conversely, the direct activation of SIRT1 by SRT1720 resulted in decreased FoxP3 expression, with no reduction in ROS levels. The pho-mTOR levels were significantly higher in Tregs after activation by SRT1720 than in those after RVL treatment. This study suggested that imbalanced changes in Tregs could be attributed to mTOR activation, in which ROS overproduction was predominantly implicated. Therefore, ROS is a key mediator for promoting Tregs instability in AAV.<\/jats:p>","DOI":"10.3389\/fimmu.2021.789740","type":"journal-article","created":{"date-parts":[[2021,12,7]],"date-time":"2021-12-07T08:47:54Z","timestamp":1638866874000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":32,"title":["Oxidative Stress Promotes Instability of Regulatory T Cells in Antineutrophil Cytoplasmic Antibody-Associated Vasculitis"],"prefix":"10.3389","volume":"12","author":[{"given":"Yasuhiro","family":"Shimojima","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Dai","family":"Kishida","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Takanori","family":"Ichikawa","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ryota","family":"Takamatsu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shun","family":"Nomura","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yoshiki","family":"Sekijima","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2021,12,7]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","DOI":"10.1038\/nrrheum.2014.103","article-title":"Pathogenesis of Antineutrophil Cytoplasmic Autoantibody-Mediated Disease","volume":"10","author":"Jennette","year":"2014","journal-title":"Nat Rev Rheumatol"},{"key":"B2","doi-asserted-by":"publisher","first-page":"91","DOI":"10.1038\/s41584-018-0145-y","article-title":"Pathogenesis and Therapeutic Interventions for ANCA-Associated Vasculitis","volume":"15","author":"Nakazawa","year":"2019","journal-title":"Nat Rev Rheumatol"},{"key":"B3","doi-asserted-by":"publisher","first-page":"64","DOI":"10.1111\/j.1365-2567.2009.03213.x","article-title":"Patients With Wegener\u2019s Granulomatosis Demonstrate a Relative Deficiency and Functional Impairment of T-Regulatory Cells","volume":"130","author":"Morgan","year":"2010","journal-title":"Immunology"},{"key":"B4","doi-asserted-by":"publisher","DOI":"10.1002\/art.37959","article-title":"Patients With Antineutrophil Cytoplasmic Antibody-Associated Vasculitis Have Defective Treg Cell Function Exacerbated by the Presence of a Suppression-Resistant Effector Cell Population","volume":"65","author":"Free","year":"2013","journal-title":"Arthritis Rheum"},{"key":"B5","doi-asserted-by":"publisher","first-page":"19","DOI":"10.1016\/j.molimm.2019.11.010","article-title":"Reduced Activated Regulatory T Cells and Imbalance of Th17\/activated Treg Cells Marks Renal Involvement in ANCA-Associated Vasculitis","volume":"118","author":"Wang","year":"2020","journal-title":"Mol Immunol"},{"key":"B6","doi-asserted-by":"publisher","first-page":"52","DOI":"10.1007\/s12016-018-8721-0","article-title":"Regulatory T Cell Plasticity and Stability and Autoimmune Diseases","volume":"58","author":"Qiu","year":"2020","journal-title":"Clin Rev Allergy Immunol"},{"key":"B7","doi-asserted-by":"publisher","DOI":"10.1016\/j.jaut.2020.102461","article-title":"The Progress and Prospect of Regulatory T Cells in Autoimmune Diseases","volume":"111","author":"Zhang","year":"2020","journal-title":"J Autoimmun"},{"key":"B8","doi-asserted-by":"publisher","first-page":"236","DOI":"10.1186\/ar3362","article-title":"T-Helper Cells as New Players in ANCA-Associated Vasculitides","volume":"13","author":"Abdulahad","year":"2011","journal-title":"Arthritis Res Ther"},{"key":"B9","doi-asserted-by":"publisher","DOI":"10.1155\/2016\/2526174","article-title":"Oxidative Stress and Treg and Th17 Dysfunction in Systemic Lupus Erythematosus","volume":"2016","author":"Yang","year":"2016","journal-title":"Oxid Med Cell Longev"},{"key":"B10","doi-asserted-by":"publisher","DOI":"10.1089\/ars.2011.4073","article-title":"Redox Regulation of T-Cell Function: From Molecular Mechanisms to Significance in Human Health and Disease","volume":"18","author":"Kesarwani","year":"2013","journal-title":"Antioxid Redox Signal"},{"key":"B11","doi-asserted-by":"publisher","first-page":"58","DOI":"10.1016\/j.molimm.2007.05.008","article-title":"Oxidative Microenvironment Exerts an Opposite Regulatory Effect on Cytokine Production by Th1 and Th2 Cells","volume":"45","author":"Frossi","year":"2008","journal-title":"Mol Immunol"},{"key":"B12","doi-asserted-by":"publisher","DOI":"10.1038\/nrrheum.2015.172","article-title":"Activation of mTOR (Mechanistic Target of Rapamycin) in Rheumatic Diseases","volume":"12","author":"Perl","year":"2016","journal-title":"Nat Rev Rheumatol"},{"key":"B13","doi-asserted-by":"publisher","first-page":"4649","DOI":"10.3390\/molecules25204649","article-title":"Mechanisms of Aging and the Preventive Effects of Resveratrol on Age-Related Diseases","volume":"25","author":"Pyo","year":"2020","journal-title":"Molecules"},{"key":"B14","doi-asserted-by":"publisher","DOI":"10.1111\/j.1749-6632.2010.05850.x","article-title":"Resveratrol and Life Extension","volume":"1215","author":"Agarwal","year":"2011","journal-title":"Ann N Y Acad Sci"},{"key":"B15","doi-asserted-by":"publisher","DOI":"10.1146\/annurev.biochem.74.082803.133500","article-title":"The Biochemistry of Sirtuins","volume":"75","author":"Sauve","year":"2006","journal-title":"Annu Rev Biochem"},{"key":"B16","doi-asserted-by":"publisher","DOI":"10.1016\/j.tibs.2008.08.001","article-title":"The Ups and Downs of SIRT1","volume":"33","author":"Kwon","year":"2008","journal-title":"Trends Biochem Sci"},{"key":"B17","doi-asserted-by":"publisher","first-page":"35","DOI":"10.1016\/j.phrs.2009.12.006","article-title":"Protein Deacetylation by SIRT1: An Emerging Key Post-Translational Modification in Metabolic Regulation","volume":"62","author":"Yu","year":"2010","journal-title":"Pharmacol Res"},{"key":"B18","doi-asserted-by":"publisher","first-page":"1","DOI":"10.1002\/art.37715","article-title":"2012 Revised International Chapel Hill Consensus Conference Nomenclature of Vasculitides","volume":"65","author":"Jennette","year":"2013","journal-title":"Arthritis Rheum"},{"key":"B19","doi-asserted-by":"publisher","DOI":"10.1136\/ard.2006.054593","article-title":"Development and Validation of a Consensus Methodology for the Classification of the ANCA-Associated Vasculitides and Polyarteritis Nodosa for Epidemiological Studies","volume":"66","author":"Watts","year":"2007","journal-title":"Ann Rheum Dis"},{"key":"B20","doi-asserted-by":"publisher","DOI":"10.1136\/ard.2008.101279","article-title":"Modification and Validation of the Birmingham Vasculitis Activity Score (Version 3)","volume":"68","author":"Mukhtyar","year":"2009","journal-title":"Ann Rheum Dis"},{"key":"B21","doi-asserted-by":"publisher","DOI":"10.1016\/j.autrev.2011.05.004","article-title":"Human FoxP3+ Regulatory T Cells in Systemic Autoimmune Diseases","volume":"10","author":"Miyara","year":"2011","journal-title":"Autoimmun Rev"},{"key":"B22","doi-asserted-by":"publisher","DOI":"10.1111\/imr.12175","article-title":"Lineage Stability and Phenotypic Plasticity of Foxp3\u207a Regulatory T Cells","volume":"259","author":"Hori","year":"2014","journal-title":"Immunol Rev"},{"key":"B23","doi-asserted-by":"publisher","DOI":"10.3389\/fimmu.2020.01269","article-title":"Molecular Insights Into Regulatory T-Cell Adaptation to Self, Environment, and Host Tissues: Plasticity or Loss of Function in Autoimmune Disease","volume":"11","author":"Brown","year":"2020","journal-title":"Front Immunol"},{"key":"B24","doi-asserted-by":"publisher","DOI":"10.1038\/nature05479","article-title":"Regulatory T-Cell Functions Are Subverted and Converted Owing to Attenuated Foxp3 Expression","volume":"445","author":"Wan","year":"2007","journal-title":"Nature"},{"key":"B25","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":"B26","doi-asserted-by":"publisher","DOI":"10.1002\/eji.200839196","article-title":"Natural Treg Cells Spontaneously Differentiate Into Pathogenic Helper Cells in Lymphopenic Conditions","volume":"39","author":"Duarte","year":"2009","journal-title":"Eur J Immunol"},{"key":"B27","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0035572","article-title":"Inflammation-Driven Reprogramming of CD4+ Foxp3+ Regulatory T Cells Into Pathogenic Th1\/Th17 T Effectors Is Abrogated by mTOR Inhibition In Vivo","volume":"7","author":"Yurchenko","year":"2012","journal-title":"PloS One"},{"key":"B28","doi-asserted-by":"publisher","DOI":"10.1002\/eji.200838904","article-title":"Loss of FOXP3 Expression in Natural Human CD4+CD25+ Regulatory T Cells Upon Repetitive In Vitro Stimulation","volume":"39","author":"Hoffmann","year":"2009","journal-title":"Eur J Immunol"},{"key":"B29","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":"B30","doi-asserted-by":"publisher","DOI":"10.1016\/j.biopha.2020.110978","article-title":"Reactive Oxygen Species in Immune Cells: A New Antitumor Target","volume":"133","author":"Wang","year":"2021","journal-title":"BioMed Pharmacother"},{"key":"B31","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0091146","article-title":"Reactive Oxygen Species Prevent Imiquimod-Induced Psoriatic Dermatitis Through Enhancing Regulatory T Cell Function","volume":"9","author":"Kim","year":"2014","journal-title":"PloS One"},{"key":"B32","doi-asserted-by":"publisher","first-page":"3157","DOI":"10.1038\/s41467-018-05676-6","article-title":"SENP3 Maintains the Stability and Function of Regulatory T Cells via BACH2 Desumoylation","volume":"9","author":"Yu","year":"2018","journal-title":"Nat Commun"},{"key":"B33","doi-asserted-by":"publisher","DOI":"10.1016\/j.imbio.2018.07.004","article-title":"Effect of Redox Status of Peripheral Blood on Immune Signature of Circulating Regulatory and Cytotoxic T Cells in Streptozotocin Induced Rodent Model of Type I Diabetes","volume":"223","author":"Anupam","year":"2018","journal-title":"Immunobiology"},{"key":"B34","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.M111.238014","article-title":"Redox Regulates Mammalian Target of Rapamycin Complex 1 (Mtorc1) Activity by Modulating the TSC1\/TSC2-Rheb GTPase Pathway","volume":"286","author":"Yoshida","year":"2011","journal-title":"J Biol Chem"},{"key":"B35","doi-asserted-by":"publisher","DOI":"10.1016\/j.immuni.2009.04.014","article-title":"The mTOR Kinase Differentially Regulates Effector and Regulatory T Cell Lineage Commitment","volume":"30","author":"Delgoffe","year":"2009","journal-title":"Immunity"},{"key":"B36","doi-asserted-by":"publisher","DOI":"10.1084\/jem.20071477","article-title":"The AKT-mTOR Axis Regulates De Novo Differentiation of CD4+Foxp3+ Cells","volume":"205","author":"Haxhinasto","year":"2008","journal-title":"J Exp Med"},{"key":"B37","doi-asserted-by":"publisher","DOI":"10.1182\/blood-2007-06-094482","article-title":"Differential Impact of Mammalian Target of Rapamycin Inhibition on CD4+CD25+Foxp3+ Regulatory T Cells Compared With Conventional CD4+ T Cells","volume":"111","author":"Zeiser","year":"2008","journal-title":"Blood"},{"key":"B38","doi-asserted-by":"publisher","first-page":"295","DOI":"10.1038\/ni.2005","article-title":"The Kinase mTOR Regulates the Differentiation of Helper T Cells Through the Selective Activation of Signaling by Mtorc1 and Mtorc2","volume":"12","author":"Delgoffe","year":"2011","journal-title":"Nat Immunol"},{"key":"B39","doi-asserted-by":"publisher","DOI":"10.1016\/j.chom.2008.02.002","article-title":"Human Immunodeficiency Virus Type 1 Tat Protein Inhibits the SIRT1 Deacetylase and Induces T Cell Hyperactivation","volume":"3","author":"Kwon","year":"2008","journal-title":"Cell Host Microbe"},{"key":"B40","doi-asserted-by":"publisher","DOI":"10.1089\/thy.2017.0286","article-title":"SIRT1-Regulated Abnormal Acetylation of FOXP3 Induces Regulatory T-Cell Function Defect in Hashimoto\u2019s Thyroiditis","volume":"28","author":"Yang","year":"2018","journal-title":"Thyroid"},{"key":"B41","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0019047","article-title":"Rapid Temporal Control of Foxp3 Protein Degradation by Sirtuin-1","volume":"6","author":"van Loosdregt","year":"2011","journal-title":"PloS One"},{"key":"B42","doi-asserted-by":"publisher","first-page":"250","DOI":"10.3390\/nu8050250","article-title":"Resveratrol and Cardiovascular Diseases","volume":"8","author":"Bonnefont-Rousselot","year":"2016","journal-title":"Nutrients"},{"key":"B43","doi-asserted-by":"publisher","DOI":"10.1016\/j.mad.2010.02.007","article-title":"Resveratrol, Sirtuins, and the Promise of a DR Mimetic","volume":"131","author":"Baur","year":"2010","journal-title":"Mech Ageing Dev"},{"key":"B44","doi-asserted-by":"publisher","first-page":"25","DOI":"10.1172\/jci73939","article-title":"mTOR: A Pharmacologic Target for Autophagy Regulation","volume":"125","author":"Kim","year":"2015","journal-title":"J Clin Invest"},{"key":"B45","doi-asserted-by":"publisher","DOI":"10.1002\/art.34502","article-title":"N-Acetylcysteine Reduces Disease Activity by Blocking Mammalian Target of Rapamycin in T Cells From Systemic Lupus Erythematosus Patients: A Randomized, Double-Blind, Placebo-Controlled Trial","volume":"64","author":"Lai","year":"2012","journal-title":"Arthritis Rheum"},{"key":"B46","doi-asserted-by":"publisher","DOI":"10.1002\/art.37893","article-title":"Attention Deficit and Hyperactivity Disorder Scores Are Elevated and Respond to N-Acetylcysteine Treatment in Patients With Systemic Lupus Erythematosus","volume":"65","author":"Garcia","year":"2013","journal-title":"Arthritis Rheum"},{"key":"B47","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.M111.283705","article-title":"Ligation of Cytotoxic T Lymphocyte Antigen-4 to T Cell Receptor Inhibits T Cell Activation and Directs Differentiation Into Foxp3+ Regulatory T Cells","volume":"287","author":"Karman","year":"2012","journal-title":"J Biol Chem"},{"key":"B48","doi-asserted-by":"publisher","DOI":"10.1016\/j.imlet.2020.06.016","article-title":"TGF-\u03b21 Maintains Foxp3 Expression and Inhibits Glycolysis in Natural Regulatory T Cells via PP2A-Mediated Suppression of mTOR Signaling","volume":"226","author":"Chen","year":"2020","journal-title":"Immunol Lett"},{"key":"B49","doi-asserted-by":"publisher","DOI":"10.1084\/jem.188.10.1849","article-title":"Engagement of Cytotoxic T Lymphocyte-Associated Antigen 4 (CTLA-4) Induces Transforming Growth Factor Beta (TGF-Beta) Production by Murine CD4(+) T Cells","volume":"188","author":"Chen","year":"1998","journal-title":"J Exp Med"}],"container-title":["Frontiers in Immunology"],"original-title":[],"link":[{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fimmu.2021.789740\/full","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2021,12,7]],"date-time":"2021-12-07T08:47:57Z","timestamp":1638866877000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fimmu.2021.789740\/full"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2021,12,7]]},"references-count":49,"alternative-id":["10.3389\/fimmu.2021.789740"],"URL":"https:\/\/doi.org\/10.3389\/fimmu.2021.789740","relation":{},"ISSN":["1664-3224"],"issn-type":[{"value":"1664-3224","type":"electronic"}],"subject":[],"published":{"date-parts":[[2021,12,7]]},"article-number":"789740"}}