Giant cell arteritis (GCA) is a systemic vasculitis mediated by an aberrant immunological response against the blood vessel wall. Although the pathogenic mechanisms that drive GCA have not yet been elucidated, there is strong evidence that CD4 T cells are key drivers of the inflammatory process occurring in this vasculitis. The aim of this study was to further delineate the role of CD4 T cells in GCA by applying single-cell RNA sequencing and T cell receptor (TCR) repertoire profiling to 114.799 circulating CD4 T cells from eight GCA patients in two different clinical states, active and in remission, and eight healthy controls. Our results revealed an expansion of cytotoxic CD4 T lymphocytes (CTLs) in active GCA patients, which expressed higher levels of cytotoxic and chemotactic genes when compared to patients in remission and controls. Accordingly, differentially expressed genes in CTLs of active patients were enriched in pathways related to granzyme-mediated apoptosis, inflammation, and the recruitment of different immune cells, suggesting a role of this cell type in the inflammatory and vascular remodelling processes occurring in GCA. CTLs also exhibited a higher clonal expansion in active patients with respect to those in remission. Drug repurposing analysis prioritized maraviroc, which targeted CTLs, as potentially repositionable for this vasculitis. In addition, effector regulatory T cells (Tregs) were decreased in GCA and showed lower expression of genes involved in their suppressive activity. These findings provide further insights into the pathogenic role of CD4 T cells in GCA and suggest targeting CTLs as a potential therapeutic option.

中文翻译：

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单细胞转录组分析揭示细胞毒性 CD4+ T 细胞在巨细胞动脉炎中的致病作用

巨细胞动脉炎（GCA）是一种由针对血管壁的异常免疫反应介导的系统性血管炎。尽管驱动 GCA 的致病机制尚未阐明，但有强有力的证据表明 CD4 T 细胞是这种血管炎炎症过程的关键驱动因素。本研究的目的是通过对来自 8 名处于两种不同临床状态的 GCA 患者的 114.799 个循环 CD4 T 细胞应用单细胞 RNA 测序和 T 细胞受体 (TCR) 谱分析，进一步阐明 CD4 T 细胞在 GCA 中的作用。和缓解期，以及八名健康对照。我们的结果显示，活动性 GCA 患者的细胞毒性 CD4 T 淋巴细胞 (CTL) 有所增加，与缓解期患者和对照患者相比，其表达更高水平的细胞毒性和趋化基因。因此，活跃患者的 CTL 中差异表达的基因在与颗粒酶介导的细胞凋亡、炎症和不同免疫细胞的招募相关的通路中富集，表明这种细胞类型在 GCA 发生的炎症和血管重塑过程中的作用。与缓解期患者相比，活动期患者的 CTL 也表现出更高的克隆扩增。药物再利用分析优先考虑了马拉韦罗，它针对 CTL，有可能重新定位治疗这种血管炎。此外，GCA 中效应调节性 T 细胞 (Treg) 减少，并且与其抑制活性相关的基因表达降低。这些发现进一步深入了解了 CD4 T 细胞在 GCA 中的致病作用，并建议将 CTL 作为潜在的治疗选择。