Department of Endocrinology, the First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, China.
MOE Key Lab for Intelligent Networks & Networks Security, School of Electronic and Information Engineering, Xi'an Jiaotong University, Xi'an, China.
Cell Mol Immunol. 2021 Mar;18(3):735-745. doi: 10.1038/s41423-020-00615-2. Epub 2021 Jan 29.
Graves' orbitopathy (GO), the most severe manifestation of Graves' hyperthyroidism (GH), is an autoimmune-mediated inflammatory disorder, and treatments often exhibit a low efficacy. CD4+ T cells have been reported to play vital roles in GO progression. To explore the pathogenic CD4+ T cell types that drive GO progression, we applied single-cell RNA sequencing (scRNA-Seq), T cell receptor sequencing (TCR-Seq), flow cytometry, immunofluorescence and mixed lymphocyte reaction (MLR) assays to evaluate CD4+ T cells from GO and GH patients. scRNA-Seq revealed the novel GO-specific cell type CD4+ cytotoxic T lymphocytes (CTLs), which are characterized by chemotactic and inflammatory features. The clonal expansion of this CD4+ CTL population, as demonstrated by TCR-Seq, along with their strong cytotoxic response to autoantigens, localization in orbital sites, and potential relationship with disease relapse provide strong evidence for the pathogenic roles of GZMB and IFN-γ-secreting CD4+ CTLs in GO. Therefore, cytotoxic pathways may become potential therapeutic targets for GO.
格雷夫斯眼病（GO）是格雷夫斯甲亢（GH）最严重的表现，是一种自身免疫介导的炎症性疾病，治疗往往疗效较低。已有报道称 CD4+T 细胞在 GO 的进展中发挥着重要作用。为了探索驱动 GO 进展的致病 CD4+T 细胞类型，我们应用单细胞 RNA 测序（scRNA-Seq）、T 细胞受体测序（TCR-Seq）、流式细胞术、免疫荧光和混合淋巴细胞反应（MLR）检测评估 GO 和 GH 患者的 CD4+T 细胞。scRNA-Seq 揭示了新型的 GO 特异性细胞类型 CD4+细胞毒性 T 淋巴细胞（CTL），其特征是趋化和炎症特征。TCR-Seq 显示该 CD4+CTL 群体的克隆扩增，以及它们对自身抗原的强烈细胞毒性反应、在眼眶部位的定位以及与疾病复发的潜在关系，为 GZMB 和 IFN-γ 分泌 CD4+CTL 在 GO 中的致病作用提供了有力证据。因此，细胞毒性途径可能成为 GO 的潜在治疗靶点。
