{"title":"Dynamic Transition of Regulatory T Cells to Cytotoxic Phenotype Amid Systemic Inflammation in Graves' Ophthalmopathy.","authors":"Zhong Liu, Shurui Ke, Zhuoxing Shi, Ming Zhou, Li Sun, Qihang Sun, Bing Xiao, Dongliang Wang, Yanjing Huang, Jinshan Lin, Huishi Wang, Qikai Zhang, Caineng Pan, Xuanwei Liang, Rongxin Chen, Zhen Mao, Xianchai Lin","doi":"10.1172/jci.insight.181488","DOIUrl":null,"url":null,"abstract":"<p><p>Graves' disease (GD) is an autoimmune condition that can progress to Graves' Ophthalmopathy (GO), leading to irreversible damage to orbital tissues and potential blindness. The pathogenic mechanism is not fully understood. In this study, we conducted single-cell multi-omics analyses on healthy individuals, GD patients without GO, newly diagnosed GO patients, and treated GO patients. Our findings revealed gradual systemic inflammation during GO progression, marked by overactivation of cytotoxic effector T cell subsets, and expansion of specific T cell receptor clones. Importantly, we observed a decline in the immunosuppressive function of activated regulatory T cells (aTreg) accompanied by a cytotoxic phenotypic transition. In vitro experiments revealed that dysfunction and transition of GO-autoreactive Treg were regulated by the yinyang1 (YY1) upon secondary stimulation of thyroid stimulating hormone receptor (TSHR) under inflammatory conditions. Furthermore, adoptive transfer experiments of GO mouse model confirmed infiltration of these cytotoxic Treg into the orbital lesion tissues. Notably, these cells were found to upregulate inflammation and promote pathogenic fibrosis of orbital fibroblasts (OFs). Our results revealed the dynamic changes in immune landscape during GO progression and provided novel insights into the instability and phenotypic transition of Treg, offering potential targets for therapeutic intervention and prevention of autoimmune diseases.</p>","PeriodicalId":14722,"journal":{"name":"JCI insight","volume":" ","pages":""},"PeriodicalIF":6.3000,"publicationDate":"2024-10-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":"0","resultStr":null,"platform":"Semanticscholar","paperid":null,"PeriodicalName":"JCI insight","FirstCategoryId":"3","ListUrlMain":"https://doi.org/10.1172/jci.insight.181488","RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"Q1","JCRName":"MEDICINE, RESEARCH & EXPERIMENTAL","Score":null,"Total":0}
引用次数: 0
Abstract
Graves' disease (GD) is an autoimmune condition that can progress to Graves' Ophthalmopathy (GO), leading to irreversible damage to orbital tissues and potential blindness. The pathogenic mechanism is not fully understood. In this study, we conducted single-cell multi-omics analyses on healthy individuals, GD patients without GO, newly diagnosed GO patients, and treated GO patients. Our findings revealed gradual systemic inflammation during GO progression, marked by overactivation of cytotoxic effector T cell subsets, and expansion of specific T cell receptor clones. Importantly, we observed a decline in the immunosuppressive function of activated regulatory T cells (aTreg) accompanied by a cytotoxic phenotypic transition. In vitro experiments revealed that dysfunction and transition of GO-autoreactive Treg were regulated by the yinyang1 (YY1) upon secondary stimulation of thyroid stimulating hormone receptor (TSHR) under inflammatory conditions. Furthermore, adoptive transfer experiments of GO mouse model confirmed infiltration of these cytotoxic Treg into the orbital lesion tissues. Notably, these cells were found to upregulate inflammation and promote pathogenic fibrosis of orbital fibroblasts (OFs). Our results revealed the dynamic changes in immune landscape during GO progression and provided novel insights into the instability and phenotypic transition of Treg, offering potential targets for therapeutic intervention and prevention of autoimmune diseases.
巴塞杜氏病(GD)是一种自身免疫性疾病,可发展为巴塞杜氏眼病(GO),导致眼眶组织不可逆转的损伤和潜在的失明。其致病机制尚不完全清楚。在这项研究中,我们对健康人、未患巴塞杜氏眼病的广东患者、新诊断的巴塞杜氏眼病患者和接受治疗的巴塞杜氏眼病患者进行了单细胞多组学分析。我们的研究结果表明,在 GO 进展过程中,全身炎症逐渐加重,细胞毒性效应 T 细胞亚群过度活化,特异性 T 细胞受体克隆扩大。重要的是,我们观察到活化调节性T细胞(aTreg)的免疫抑制功能下降,并伴有细胞毒性表型转变。体外实验显示,在炎症条件下,当促甲状腺激素受体(TSHR)二次刺激时,GO-自反应Treg的功能障碍和转变受阴阳1(YY1)的调控。此外,GO小鼠模型的收养转移实验证实了这些细胞毒性Treg渗入眼眶病变组织。值得注意的是,这些细胞会上调炎症反应,并促进眼眶成纤维细胞(OFs)的致病性纤维化。我们的研究结果揭示了GO进展过程中免疫格局的动态变化,并对Treg的不稳定性和表型转变提供了新的见解,为治疗干预和预防自身免疫性疾病提供了潜在靶点。
期刊介绍:
JCI Insight is a Gold Open Access journal with a 2022 Impact Factor of 8.0. It publishes high-quality studies in various biomedical specialties, such as autoimmunity, gastroenterology, immunology, metabolism, nephrology, neuroscience, oncology, pulmonology, and vascular biology. The journal focuses on clinically relevant basic and translational research that contributes to the understanding of disease biology and treatment. JCI Insight is self-published by the American Society for Clinical Investigation (ASCI), a nonprofit honor organization of physician-scientists founded in 1908, and it helps fulfill the ASCI's mission to advance medical science through the publication of clinically relevant research reports.