Disease-specific T cell receptors maintain pathogenic T helper cell responses in postinfectious Lyme arthritis.

IF 13.3 1区 医学 Q1 MEDICINE, RESEARCH & EXPERIMENTAL Journal of Clinical Investigation Pub Date : 2024-07-04 DOI:10.1172/JCI179391
Johannes Dirks, Jonas Fischer, Julia Klaussner, Christine Hofmann, Annette Holl-Wieden, Viktoria Buck, Christian Klemann, Hermann J Girschick, Ignazio Caruana, Florian Erhard, Henner Morbach
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Abstract

BACKGROUNDAntibiotic-Refractory Lyme Arthritis (ARLA) involves a complex interplay of T cell responses targeting Borrelia burgdorferi antigens progressing toward autoantigens by epitope spreading. However, the precise molecular mechanisms driving the pathogenic T cell response in ARLA remain unclear. Our aim was to elucidate the molecular program of disease-specific Th cells.METHODSUsing flow cytometry, high-throughput T cell receptor (TCR) sequencing, and scRNA-Seq of CD4+ Th cells isolated from the joints of patients with ARLA living in Europe, we aimed to infer antigen specificity through unbiased analysis of TCR repertoire patterns, identifying surrogate markers for disease-specific TCRs, and connecting TCR specificity to transcriptional patterns.RESULTSPD-1hiHLA-DR+CD4+ effector T cells were clonally expanded within the inflamed joints and persisted throughout disease course. Among these cells, we identified a distinct TCR-β motif restricted to HLA-DRB1*11 or *13 alleles. These alleles, being underrepresented in patients with ARLA living in North America, were unexpectedly prevalent in our European cohort. The identified TCR-β motif served as surrogate marker for a convergent TCR response specific to ARLA, distinguishing it from other rheumatic diseases. In the scRNA-Seq data set, the TCR-β motif particularly mapped to peripheral T helper (TPH) cells displaying signs of sustained proliferation, continuous TCR signaling, and expressing CXCL13 and IFN-γ.CONCLUSIONBy inferring disease-specific TCRs from synovial T cells we identified a convergent TCR response in the joints of patients with ARLA that continuously fueled the expansion of TPH cells expressing a pathogenic cytokine effector program. The identified TCRs will aid in uncovering the major antigen targets of the maladaptive immune response.FUNDINGSupported by the German Research Foundation (DFG) MO 2160/4-1; the Federal Ministry of Education and Research (BMBF; Advanced Clinician Scientist-Program INTERACT; 01EO2108) embedded in the Interdisciplinary Center for Clinical Research (IZKF) of the University Hospital Würzburg; the German Center for Infection Research (DZIF; Clinical Leave Program; TI07.001_007) and the Interdisciplinary Center for Clinical Research (IZKF) Würzburg (Clinician Scientist Program, Z-2/CSP-30).

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疾病特异性 T 细胞受体可维持感染后莱姆关节炎的致病性 T 辅助细胞反应。
背景:抗生素难治性莱姆关节炎(ARLA)涉及以布氏杆菌抗原为靶点的 T 细胞反应的复杂相互作用,这些 T 细胞反应通过表位扩散向自身抗原发展。然而,驱动 ARLA 中致病性 T 细胞反应的确切分子机制仍不清楚。我们的目的是阐明疾病特异性Th细胞的分子程序:方法:我们使用流式细胞术、高通量 T 细胞受体(TCR)测序和 scRNA-seq 对从欧洲 ARLA 患者关节中分离出的 CD4+ Th 细胞进行研究,旨在通过对 TCR 重排模式的无偏见分析来推断抗原特异性,确定疾病特异性 TCR 的替代标记物,并将 TCR 特异性与转录模式联系起来:结果:PD-1hiHLA-DR+CD4+效应T细胞在发炎关节内克隆扩增,并在整个病程中持续存在。在这些细胞中,我们发现了局限于 HLA-DRB1*11 或 *13 等位基因的独特 TCRβ motif。这些等位基因在北美的 ARLA 患者中比例较低,但在我们的欧洲队列中却意外地普遍存在。所发现的 TCRβ 矩阵可作为 ARLA 特异性 TCR 反应的替代标记,将 ARLA 与其他风湿性疾病区分开来。在scRNA-seq数据集中,TCRβ基序特别映射到外周T辅助细胞(TPH),这些细胞显示出持续增殖、持续TCR信号转导以及表达CXCL13和IFN-γ的迹象:通过推断滑膜 T 细胞中的疾病特异性 TCR,我们在 ARLA 患者的关节中发现了一种趋同的 TCR 反应,这种反应不断促进表达致病细胞因子效应程序的 TPH 细胞的增殖。鉴定出的TCR将有助于发现适应不良免疫反应的主要抗原靶点:由德国研究基金会(DFG)MO 2160/4-1、维尔茨堡大学医院临床研究跨学科中心(IZKF)嵌入的联邦教育与研究部(BMBF;高级临床科学家计划 INTERACT;01EO2108)、德国感染研究中心(DZIF;临床休假计划;TI07.001_007)和维尔茨堡临床研究跨学科中心(IZKF)(临床科学家计划,Z-2/CSP-30)资助。
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来源期刊
Journal of Clinical Investigation
Journal of Clinical Investigation 医学-医学:研究与实验
CiteScore
24.50
自引率
1.30%
发文量
1034
审稿时长
2 months
期刊介绍: The Journal of Clinical Investigation, established in 1924 by the ASCI, is a prestigious publication that focuses on breakthroughs in basic and clinical biomedical science, with the goal of advancing the field of medicine. With an impressive Impact Factor of 15.9 in 2022, it is recognized as one of the leading journals in the "Medicine, Research & Experimental" category of the Web of Science. The journal attracts a diverse readership from various medical disciplines and sectors. It publishes a wide range of research articles encompassing all biomedical specialties, including Autoimmunity, Gastroenterology, Immunology, Metabolism, Nephrology, Neuroscience, Oncology, Pulmonology, Vascular Biology, and many others. The Editorial Board consists of esteemed academic editors who possess extensive expertise in their respective fields. They are actively involved in research, ensuring the journal's high standards of publication and scientific rigor.
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