{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,7]],"date-time":"2026-10-07T00:26:25Z","timestamp":1791332785917,"version":"4.3.1"},"reference-count":49,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2025,8,22]],"date-time":"2025-08-22T00:00:00Z","timestamp":1755820800000},"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:sec><jats:title>Background<\/jats:title><jats:p>Regulatory T cells (Tregs) are found to be critical for maintaining immune tolerance to self-antigens; however, their status in primary Sj\u00f6gren\u2019s syndrome (pSS) remains unclear. We investigated alterations in the abundance of peripheral Tregs in a large pSS cohort and their implications for patients.<\/jats:p><\/jats:sec><jats:sec><jats:title>Methods<\/jats:title><jats:p>Levels of CD4+CD25+FOXP3+Treg cells in the peripheral blood of 624 patients with pSS, and 93 healthy controls (HCs) were detected using modified flow cytometry (FCM). We then performed transcriptome sequencing of CD4+CD25+CD127-Treg cells, and used droplet digital PCR (ddPCR) to validate that the apoptosis-related genes were found in the sorted Treg cells. Apoptosis of CD4+CD25+CD127-Treg cells was verified using 7-AAD and annexin-V staining. We performed FOXP3\/activated caspase-3 double immunohistochemistry to characterize features of the labial salivary glands.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>The peripheral abundance of Treg cells from relapsing pSS patients was significantly contracted, especially in patients with high disease activity. We identified 187 upregulated and 674 downregulated DEGs in sorted Tregs from pSS patients, including five apoptotic pathway hub genes (XIAP, CASP3, CASP10, NFKBIA, and PMAIP1)-a finding consistent with increased Treg apoptosis in pSS. Active caspase-3 was detected in FOXP3+ cells within the minor labial salivary gland tissue of pSS patients. Higher levels of active Caspase-3 were correlated with lower Treg cell numbers. Interestingly, although the downregulation of the PI3K\/AKT signaling pathway did not reach statistical significance, this vital pro-survival axis may still contribute to Treg impairment in pSS.<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusions<\/jats:title><jats:p>These data suggest that the decreased peripheral abundance and increased apoptosis of Treg cells play an important role in the pathogenesis of pSS. Therefore, approaches for increasing Treg numbers <jats:italic>in vivo<\/jats:italic> could provide precise pSS therapy.<\/jats:p><\/jats:sec>","DOI":"10.3389\/fimmu.2025.1603305","type":"journal-article","created":{"date-parts":[[2025,8,22]],"date-time":"2025-08-22T05:27:43Z","timestamp":1755840463000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":4,"title":["Reduced circulating regulatory T cells in primary Sj\u00f6gren\u2019s syndrome: the contribution of enhanced apoptosis and impaired survival"],"prefix":"10.3389","volume":"16","author":[{"given":"Yanlin","family":"Wang","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yuhan","family":"Jia","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hui","family":"Guo","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Min","family":"Feng","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yan","family":"Qin","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zhaojun","family":"Liang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xiangcong","family":"Zhao","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chong","family":"Gao","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jing","family":"Luo","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2025,8,22]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","DOI":"10.1056\/NEJMcp1702514","article-title":"Primary sj\u00f6gren\u2019s syndrome","volume":"378","author":"Mariette","year":"2018","journal-title":"N Engl J Med"},{"key":"B2","doi-asserted-by":"publisher","DOI":"10.1136\/annrheumdis-2019-216428","article-title":"Elevated EPSTI1 promote B cell hyperactivation through NF-\u03baB signalling in patients with primary Sj\u00f6gren\u2019s syndrome","volume":"79","author":"Sun","year":"2020","journal-title":"Ann Rheum Dis"},{"key":"B3","doi-asserted-by":"publisher","first-page":"3","DOI":"10.1136\/annrheumdis-2019-216114","article-title":"EULAR recommendations for the management of Sj\u00f6gren\u2019s syndrome with topical and systemic therapies","volume":"79","author":"Ramos-Casals","year":"2020","journal-title":"Ann Rheum Dis"},{"key":"B4","doi-asserted-by":"publisher","DOI":"10.1016\/j.jaut.2014.02.006","article-title":"Sj\u00f6gren\u2019s syndrome: where do we stand, and where shall we go","volume":"51","author":"Cornec","year":"2014","journal-title":"J Autoimmun"},{"key":"B5","doi-asserted-by":"publisher","DOI":"10.1038\/s41584-021-00707-x","article-title":"Interleukin-2 and regulatory T cells in rheumatic diseases","volume":"17","author":"Kolios","year":"2021","journal-title":"Nat Rev Rheumatol"},{"key":"B6","doi-asserted-by":"publisher","first-page":"487","DOI":"10.1038\/s41584-021-00639-6","article-title":"Insights into the biology and therapeutic implications of TNF and regulatory T cells","volume":"17","author":"Salomon","year":"2021","journal-title":"Nat Rev Rheumatol"},{"key":"B7","doi-asserted-by":"publisher","DOI":"10.1016\/j.autrev.2014.10.012","article-title":"Regulatory T-cells in autoimmune diseases: challenges, controversies and\u2013yet\u2013unanswered questions","volume":"14","author":"Grant","year":"2015","journal-title":"Autoimmun Rev"},{"key":"B8","doi-asserted-by":"publisher","DOI":"10.1016\/j.jbspin.2020.04.013","article-title":"Infliximab induces clinical resolution of sacroiliitis that coincides with increased circulating FOXP3+ T cells in a patient with IPEX syndrome","volume":"87","author":"Boschetti","year":"2020","journal-title":"Joint Bone Spine"},{"key":"B9","doi-asserted-by":"publisher","DOI":"10.1038\/s41590-021-01001-4","article-title":"Regulatory T cells function in established systemic inflammation and reverse fatal autoimmunity","volume":"22","author":"Hu","year":"2021","journal-title":"Nat Immunol"},{"key":"B10","doi-asserted-by":"publisher","DOI":"10.1093\/humrep\/det316","article-title":"The success of assisted reproduction technologies in relation to composition of the total regulatory T cell (Treg) pool and different Treg subsets","volume":"28","author":"Schlossberger","year":"2013","journal-title":"Hum Reprod"},{"key":"B11","doi-asserted-by":"publisher","DOI":"10.1016\/j.molimm.2021.01.014","article-title":"Double-negative T cells are absolutely elevated in patients with antineutrophil cytoplasmic autoantibody-associated vasculitis","volume":"132","author":"Qin","year":"2021","journal-title":"Mol Immunol"},{"key":"B12","doi-asserted-by":"publisher","DOI":"10.1136\/rmdopen-2014-000022","article-title":"EULAR Sj\u00f6gren\u2019s syndrome Dis activity index (ESSDAI): user guide. RMD Open","volume":"1","author":"Seror","year":"2015"},{"key":"B13","doi-asserted-by":"publisher","DOI":"10.1016\/j.humimm.2015.12.004","article-title":"Transcriptome profiling of human FoxP3+ regulatory T cells","volume":"77","author":"Bhairavabhotla","year":"2016","journal-title":"Hum Immunol"},{"key":"B14","doi-asserted-by":"publisher","DOI":"10.1038\/s41590-020-0784-4","article-title":"Functional CRISPR dissection of gene networks controlling human regulatory T cell identity","volume":"21","author":"Schumann","year":"2020","journal-title":"Nat Immunol"},{"key":"B15","doi-asserted-by":"publisher","first-page":"34","DOI":"10.1186\/s12935-021-02441-6","article-title":"Periostin promotes the proliferation and metastasis of osteosarcoma by increasing cell survival and activates the PI3K\/Akt pathway","volume":"22","author":"Xu","year":"2022","journal-title":"Cancer Cell Int"},{"key":"B16","doi-asserted-by":"publisher","DOI":"10.1016\/j.jcyt.2017.05.005","article-title":"The influence of temperature treatment before cryopreservation on the viability and potency of cryopreserved and thawed CD34+ and CD45+ cord blood cells","volume":"19","author":"Schwandt","year":"2017","journal-title":"Cytotherapy"},{"key":"B17","doi-asserted-by":"publisher","DOI":"10.1039\/d0sc00785d","article-title":"Type I photosensitizers based onxphosphindole oxide for photodynamic therapy: apoptosis and autophagy induced by endoplasmic reticulum stress","volume":"11","author":"Zhuang","year":"2020","journal-title":"Chem Sci"},{"key":"B18","doi-asserted-by":"publisher","first-page":"57","DOI":"10.1007\/s11418-017-1117-2","article-title":"The anti-tumor effect of pachymic acid on osteosarcoma cells by inducing PTEN and Caspase 3\/7-dependent apoptosis","volume":"72","author":"Wen","year":"2018","journal-title":"J Nat Med"},{"key":"B19","doi-asserted-by":"publisher","DOI":"10.3389\/fimmu.2020.616949","article-title":"The complex role of regulatory T cells in immunity and aging","volume":"11","author":"Rocamora-Reverte","year":"2020","journal-title":"Front Immunol"},{"key":"B20","doi-asserted-by":"publisher","first-page":"8","DOI":"10.1111\/j.0105-2896.2006.00427.x","article-title":"Foxp3+ CD25+ CD4+ natural regulatory T cells in dominant self-tolerance and autoimmune disease","volume":"212","author":"Sakaguchi","year":"2006","journal-title":"Immunol Rev"},{"key":"B21","doi-asserted-by":"publisher","DOI":"10.1016\/j.molimm.2024.08.003","article-title":"Altered characteristics of regulatory T cells in target tissues of Sj\u00f6gren's syndrome in murine models","volume":"174","author":"Zhou","year":"2024","journal-title":"Mol Immunol"},{"key":"B22","doi-asserted-by":"publisher","first-page":"e147566","DOI":"10.1172\/JCI147566","article-title":"The FoxO4\/DKK3 axis represses IFN-gamma expression by Th1 cells and limits antimicrobial immunity","volume":"132","author":"Chen","year":"2022","journal-title":"J Clin Invest"},{"key":"B23","doi-asserted-by":"publisher","first-page":"59","DOI":"10.1186\/s12943-022-01516-w","article-title":"BCL-2 expression promotes immunosuppression in chronic lymphocytic leukemia by enhancing regulatory T cell differentiation and cytotoxic T cell exhaustion","volume":"21","author":"Liu","year":"2022","journal-title":"Mol Cancer"},{"key":"B24","doi-asserted-by":"publisher","first-page":"1183","DOI":"10.1038\/s41467-019-08959-8","article-title":"Tissue resident and follicular Treg cell differentiation is regulated by CRAC channels","volume":"10","author":"Vaeth","year":"2019","journal-title":"Nat Commun"},{"key":"B25","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.1207354109","article-title":"STIM1 and STIM2 protein deficiency in T lymphocytes underlies development of the exocrine gland autoimmune disease, Sjogren\u2019s syndrome","volume":"109","author":"Cheng","year":"2012","journal-title":"Proc Natl Acad Sci U.S.A"},{"key":"B26","doi-asserted-by":"publisher","DOI":"10.1111\/j.1751-1097.2007.00223.x","article-title":"25 years of UV-induced immunosuppression mediated by T cells-from disregarded T suppressor cells to highly respected regulatory T cells","volume":"84","author":"Schwarz","year":"2008","journal-title":"Photochem Photobiol"},{"key":"B27","doi-asserted-by":"publisher","DOI":"10.1136\/annrheumdis-2018-213036","article-title":"Short-term and low-dose IL-2 therapy restores the Th17\/Treg balance in the peripheral blood of patients with primary Sj\u00f6gren\u2019s syndrome","volume":"77","author":"Miao","year":"2018","journal-title":"Ann Rheum Dis"},{"key":"B28","doi-asserted-by":"publisher","first-page":"68","DOI":"10.1111\/imm.12351","article-title":"The effect of mTOR inhibition on Th17 and Treg differentiation in vitro and in vivo in kidney transplant recipients","volume":"144","author":"Kim","year":"2015","journal-title":"Immunology"},{"key":"B29","doi-asserted-by":"publisher","first-page":"39","DOI":"10.1002\/eji.201948131","article-title":"Treg cell therapy: How cell heterogeneity can make the difference","volume":"51","author":"Giganti","year":"2021","journal-title":"Eur J Immunol"},{"key":"B30","doi-asserted-by":"publisher","DOI":"10.3238\/arztebl.2017.0354","article-title":"The diagnosis and treatment of sj\u00f6gren\u2019s syndrome","volume":"114","author":"Stefanski","year":"2017","journal-title":"Dtsch Arztebl Int"},{"key":"B31","doi-asserted-by":"publisher","first-page":"152215","DOI":"10.1016\/j.semarthrit.2023.152215","article-title":"Temporomandibular disorders in immune-mediated rheumatic diseases of the adult: A systematic review","volume":"61","author":"Hysa","year":"2023","journal-title":"Semin Arthritis Rheum"},{"key":"B32","doi-asserted-by":"publisher","DOI":"10.1136\/gut.2010.217117","article-title":"Apoptosis of regulatory T lymphocytes is increased in chronic inflammatory bowel disease and reversed by anti-TNF\u03b1 treatment","volume":"60","author":"Veltkamp","year":"2011","journal-title":"Gut"},{"key":"B33","doi-asserted-by":"publisher","first-page":"e24272","DOI":"10.1371\/journal.pone.0024272","article-title":"Impaired thymic export and apoptosis contribute to regulatory T-cell defects in patients with chronic heart failure","volume":"6","author":"Tang","year":"2011","journal-title":"PloS One"},{"key":"B34","doi-asserted-by":"publisher","first-page":"3219","DOI":"10.1038\/s41419-017-0010-y","article-title":"Increased apoptosis of regulatory T cells in patients with active autoimmune hepatitis","volume":"8","author":"John","year":"2017","journal-title":"Cell Death Dis"},{"key":"B35","doi-asserted-by":"publisher","first-page":"35","DOI":"10.1016\/s0165-6147(98)01277-2","article-title":"The pharmacology of apoptosis","volume":"20","author":"Kinloch","year":"1999","journal-title":"Trends Pharmacol Sci"},{"key":"B36","doi-asserted-by":"publisher","DOI":"10.1053\/gast.2002.32996","article-title":"Critical role of caspases in the regulation of apoptosis and proliferation of mucosal T cells","volume":"122","author":"Sturm","year":"2002","journal-title":"Gastroenterology"},{"key":"B37","doi-asserted-by":"publisher","first-page":"154015","DOI":"10.1016\/j.phymed.2022.154015","article-title":"Activation of mitochondrial-associated apoptosis signaling pathway and inhibition of PI3K\/Akt\/mTOR signaling pathway by voacamine suppress breast cancer progression","volume":"99","author":"Zuo","year":"2022","journal-title":"Phytomedicine"},{"key":"B38","doi-asserted-by":"publisher","DOI":"10.1016\/j.immuni.2024.04.002","article-title":"Adipose-tissue Treg cells restrain differentiation of stromal adipocyte precursors to promote insulin sensitivity and metabolic homeostasis","volume":"57","author":"Wang","year":"2024","journal-title":"Immunity"},{"key":"B39","doi-asserted-by":"publisher","DOI":"10.1038\/nm.2385","article-title":"Caspase 3-mediated stimulation of tumor cell repopulation during cancer radiotherapy","volume":"17","author":"Huang","year":"2011","journal-title":"Nat Med"},{"key":"B40","doi-asserted-by":"publisher","first-page":"434","DOI":"10.1007\/s00604-018-2980-6","article-title":"Advances in nanomaterial based optical biosensing and bioimaging of apoptosis via caspase-3 activity: a review","volume":"185","author":"Khalilzadeh","year":"2018","journal-title":"Mikrochim Acta"},{"key":"B41","doi-asserted-by":"publisher","DOI":"10.1016\/j.ymthe.2020.09.024","article-title":"A Nuclear Long Non-Coding RNA LINC00618 Accelerates Ferroptosis in a Manner Dependent upon Apoptosis","volume":"29","author":"Wang","year":"2021","journal-title":"Mol Ther"},{"key":"B42","doi-asserted-by":"publisher","DOI":"10.3390\/ijms23073691","article-title":"Metazoans and intrinsic apoptosis: an evolutionary analysis of the bcl-2 family","volume":"23","author":"Suraweera","year":"2022","journal-title":"Int J Mol Sci"},{"key":"B43","doi-asserted-by":"publisher","first-page":"1","DOI":"10.1046\/j.1471-4159.1998.70010001.x","article-title":"Presenilins, the endoplasmic reticulum, and neuronal apoptosis in Alzheimer\u2019s disease","volume":"70","author":"Mattson","year":"1998","journal-title":"J Neurochem"},{"key":"B44","doi-asserted-by":"publisher","DOI":"10.1016\/j.canlet.2015.11.032","article-title":"Resveratrol triggers ER stress-mediated apoptosis by disrupting N-linked glycosylation of proteins in ovarian cancer cells","volume":"371","author":"Gwak","year":"2016","journal-title":"Cancer Lett"},{"key":"B45","doi-asserted-by":"publisher","DOI":"10.1007\/s00204-016-1835-3","article-title":"Bilirubin-induced ER stress contributes to the inflammatory response and apoptosis in neuronal cells","volume":"91","author":"Qaisiya","year":"2017","journal-title":"Arch Toxicol"},{"key":"B46","doi-asserted-by":"publisher","first-page":"1338","DOI":"10.1186\/s12885-022-10248-5","article-title":"HERPUD1 promotes ovarian cancer cell survival by sustaining autophagy and inhibit apoptosis via PI3K\/AKT\/mTOR and p38 MAPK signaling pathways","volume":"22","author":"Nie","year":"2022","journal-title":"BMC Cancer"},{"key":"B47","doi-asserted-by":"publisher","DOI":"10.1016\/j.bbrc.2017","article-title":"MicroRNA-384-mediated Herpud1 upregulation promotes angiotensin II-induced endothelial cell apoptosis","volume":"488","author":"Lin","year":"2017","journal-title":"Biochem Biophys Res Commun"},{"key":"B48","doi-asserted-by":"publisher","first-page":"e0174839","DOI":"10.1371\/journal.pone.0174839","article-title":"MiR-9-3p augments apoptosis induced by H2O2 through down regulation of Herpud1 in glioma","volume":"12","author":"Yang","year":"2017","journal-title":"PloS One"},{"key":"B49","doi-asserted-by":"publisher","DOI":"10.1002\/hep4.1032","article-title":"Up-regulation of golgi \u03b1-mannosidase IA and down-regulation of golgi \u03b1-mannosidase IC activates unfolded protein response during hepatocarcinogenesis","volume":"1","author":"Tu","year":"2017","journal-title":"Hepatol Commun"}],"container-title":["Frontiers in Immunology"],"original-title":[],"link":[{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fimmu.2025.1603305\/full","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,8,22]],"date-time":"2025-08-22T05:27:44Z","timestamp":1755840464000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fimmu.2025.1603305\/full"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2025,8,22]]},"references-count":49,"alternative-id":["10.3389\/fimmu.2025.1603305"],"URL":"https:\/\/doi.org\/10.3389\/fimmu.2025.1603305","relation":{},"ISSN":["1664-3224"],"issn-type":[{"value":"1664-3224","type":"electronic"}],"subject":[],"published":{"date-parts":[[2025,8,22]]},"article-number":"1603305"}}