Felix Beck, Phuong Nguyen, Anne Hoffmann, Lucie Loyal, Andreas Thiel, Marc Melzer, Hannah Apel, Matthias Pierer, Marco Krasselt, Olga Seifert, Anne-Marie Glimm, Tobias Hagemann, Kathrin Rothe, Ulf Wagner
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引用次数: 0
Abstract
Objectives: CD4+CD8+ T cells are increased in patients with rheumatoid arthritis (RA). They are not only associated with joint erosions in established disease, but are also present in the pre-clinical stages of RA. This study aims to further investigate their expansion in the context of T cell clonality in patients with RA, as well as their responsiveness to T cell targeted treatment.
Methods: Single-cell-(sc)RNA- and scTCR-sequencing data were used to determine co-receptor expression and T cell receptor sequences to assess clonality of CD4+CD8+ T cells in RA (n=3) patients and healthy controls (n=2). Peripheral CD4+CD8+ T cells and their subpopulations were measured in patients with RA (n=53), PsA (n=52) and healthy donors (n=50) using flow cytometry. In addition, changes in CD4+CD8+ T cell frequency were prospectively followed in RA patients receiving therapy with abatacept for 12 weeks.
Results: We observed an increase of CD4+ T cells expressing CD8α in RA patients, both in comparison to PsA patients and to healthy controls. Clonality analysis revealed, that these CD4+CD8αlow T cells are part of large T cell clones, which cluster separately from CD4+CD8- T cell clones in the scRNA-seq gene expression analysis. Treatment with abatacept significantly reduced the frequency of peripheral CD4+CD8αlow T cells, and this was linked to reduction in disease activity.
Conclusion: In RA, clonal expansion of CD4+ T cell clones culminates in the emergence of peripheral CD4+CD8αlow T cells, which are associated with disease activity and diminished upon abatacept treatment, and which could contribute to disease pathogenesis.
目的:类风湿性关节炎(RA)患者体内的 CD4+CD8+ T 细胞增多。它们不仅与已确诊疾病的关节侵蚀有关,而且还存在于 RA 的临床前期。本研究旨在进一步研究它们在 RA 患者 T 细胞克隆性背景下的扩增及其对 T 细胞靶向治疗的反应性:方法:利用单细胞(sc)RNA和scTCR测序数据确定共受体表达和T细胞受体序列,以评估RA患者(3人)和健康对照组(2人)CD4+CD8+ T细胞的克隆性。使用流式细胞术测量了RA患者(53人)、PsA患者(52人)和健康供体(50人)的外周CD4+CD8+ T细胞及其亚群。此外,还对接受阿帕他赛治疗 12 周的 RA 患者的 CD4+CD8+ T 细胞频率变化进行了前瞻性跟踪:结果:我们观察到,与 PsA 患者和健康对照组相比,RA 患者中表达 CD8α 的 CD4+ T 细胞有所增加。克隆性分析显示,这些CD4+CD8α低表达的T细胞是大T细胞克隆的一部分,在scRNA-seq基因表达分析中,它们与CD4+CD8-T细胞克隆分开聚集。阿帕他赛治疗可明显降低外周CD4+CD8α低T细胞的频率,这与疾病活动的减少有关:结论:在RA患者中,CD4+ T细胞克隆的扩增最终导致了外周CD4+CD8α低T细胞的出现,这些细胞与疾病活动有关,并在阿帕他赛治疗后减少,这可能有助于疾病的发病机制。
期刊介绍:
Arthritis & Rheumatology is the official journal of the American College of Rheumatology and focuses on the natural history, pathophysiology, treatment, and outcome of rheumatic diseases. It is a peer-reviewed publication that aims to provide the highest quality basic and clinical research in this field. The journal covers a wide range of investigative areas and also includes review articles, editorials, and educational material for researchers and clinicians. Being recognized as a leading research journal in rheumatology, Arthritis & Rheumatology serves the global community of rheumatology investigators and clinicians.