ORIGINAL RESEARCH article
Front. Immunol.
Sec. Autoimmune and Autoinflammatory Disorders : Autoimmune Disorders
Volume 16 - 2025 | doi: 10.3389/fimmu.2025.1603305
This article is part of the Research TopicT Regulatory Cells: Mechanisms and Therapeutical AdvancesView all articles
Reduced circulating regulatory T cells in primary Sjögren's syndrome: the contribution of enhanced apoptosis and impaired survival
Provisionally accepted
- 1Second Hospital of Shanxi Medical University, Taiyuan, China
- 2Deaprtment of Pathology, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts, United States
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Background: Regulatory T cells (Tregs) are found to be critical for the maintenance of immune tolerance towards self-antigens, but their statue in primary Sjögren's syndrome (pSS) remains elusive. We therefore investigated alteration in the peripheral Treg peripheral abundance during a large cohort of pSS and its implication in the patients.Methods: Levels of CD4+CD25+FOXP3+Treg cells in the peripheral blood of 624 patients with pSS, and 93 healthy controls (HCs) were detected by modified flow cytometry (FCM). Then we performed transcriptome sequencing of CD4+CD25+CD127-Treg cells, then droplet digital PCR (ddPCR) was used to validate apoptosis-related genes were found in sorted Treg cells. Apoptosis of CD4+CD25+CD127-Treg cells was verified by 7-AAD and annexin-V staining.FOXP3/activated caspase-3 double immunohistochemistry were performed to characterize features of labial salivary glands.The peripheral abundance of Treg cells from relapsing pSS patients was significantly contracted, especially the patients with high disease activity. A total of 187 upregulated and 674 downregulated differently expressed genes (DEGs) in sorted pSS were identified, including five hub genes (XIAP, CASP3, CASP10, NFKB1A, and PMAIP1) in apoptotic pathway, which was consistent with the more apoptotic Tregs in pSS. Active Caspase-3 was found in tissue FOXP3+ cells in pSS small labial gland. The higher levels of active Caspase-3 were obviously correlated with lower Treg cell number. Interestingly, although the downregulation of PI3K/AKT signaling did not achieve statistical significance, this vital pro-survival axis may still contribute to Treg impairment in pSS.Conclusions: These data suggest that decreased peripheral abundance and increased apoptosis of Treg cells play an important role in the pathogenesis of pSS. Therefore, approaches for increasing Treg numbers in vivo could provide a precise therapy for pSS.
Keywords: primary Sjögren's syndrome, regulatory T cells, Apoptosis, Caspase3, Effector T cells (Teffs)
Received: 31 Mar 2025; Accepted: 22 Jul 2025.
Copyright: © 2025 Wang, Jia, Guo, Feng, Qin, Liang, Zhao, Gao and Luo. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) or licensor are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
* Correspondence: Jing Luo, Second Hospital of Shanxi Medical University, Taiyuan, China
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