Gong Zhen, Xu Hongxiang, Zhang Qiao, Wang Guirong, Fan Lin, Wang Zilu, Fan Lichao, Liu Chang, Yu Yanhong, Liu Zhou, Zhou Qiang, Xiao Huasheng, Hou Rui, Zhao Ying, Chen Yu, Xie Jianping
Institute of Modern Biopharmaceuticals, School of Life Sciences, Southwest University, Chongqing, China.
Department of Clinical Laboratory, The Second Affiliated Hospital of Anhui Medical University, Hefei, Anhui, China.
Front Immunol. 2025 Feb 28;16:1527592. doi: 10.3389/fimmu.2025.1527592. eCollection 2025.
Hematogenous disseminated tuberculosis (DTB) has an unclear etiology that likely involves multiple factors. Understanding the underlying immunological characteristics of DTB is crucial for elucidating its pathogenesis.
We conducted single-cell RNA transcriptome and T cell receptor (TCR) sequencing on samples from seven DTB patients. Additionally, we integrated and analyzed data from two published profiles of latent TB infection, three active TB cases, and two healthy controls.
Our analysis revealed a significantly higher proportion of inflammatory immune cells (e.g., monocytes and macrophages) in DTB patients, along with a notably lower abundance of various lymphocytes (including T cells, B cells, and plasma cells), suggesting that lymphopenia is a prominent feature of the disease. T cell pseudotime analysis indicated a decrease in the expression of most hypervariable genes over time, pointing to T cell functional exhaustion. Furthermore, a marked absence of mucosal-associated invariant T (MAIT) cells was observed in the peripheral blood of DTB patients. In the TCR repertoire, specific polymorphisms (TRAV9-2, TRAV13-1, TRBV20-1, and TRBV5-1) and dominant clones (TRAJ49, TRBJ2-7, and TRBJ2-1) were identified. Analysis of the complementarity determining region 3 (CDR3) showed that the most frequent combination was TRAV1-2/TRAJ33, with the motif "CAAMD" being significantly reduced in DTB patients.
These findings suggest that lymphopenia and T cell exhaustion, along with unique TCR signatures, may play critical roles in DTB pathogenesis. The reduced "CAAMD" motif and altered TCR clonotypes provide novel insights into the complex cellular dynamics associated with the disease, potentially offering new avenues for targeted immunological interventions.
血行播散型肺结核（DTB）的病因尚不明确，可能涉及多种因素。了解DTB潜在的免疫学特征对于阐明其发病机制至关重要。
我们对7例DTB患者的样本进行了单细胞RNA转录组和T细胞受体（TCR）测序。此外，我们整合并分析了来自两个已发表的潜伏性结核感染、3例活动性肺结核病例和2例健康对照的数据集。
我们的分析显示，DTB患者中炎性免疫细胞（如单核细胞和巨噬细胞）的比例显著更高，而各种淋巴细胞（包括T细胞、B细胞和浆细胞）的丰度则明显更低，这表明淋巴细胞减少是该疾病的一个突出特征。T细胞拟时间分析表明，随着时间的推移，大多数高变基因的表达下降，表明T细胞功能耗竭。此外，在DTB患者的外周血中观察到黏膜相关恒定T细胞（MAIT）明显缺失。在TCR库中，鉴定出了特定的多态性（TRAV9-2、TRAV13-1、TRBV20-1和TRBV5-1）和优势克隆（TRAJ49、TRBJ2-7和TRBJ2-1）。互补决定区3（CDR3）分析表明，最常见的组合是TRAV1-2/TRAJ33，且“CAAMD”基序在DTB患者中显著减少。
这些发现表明，淋巴细胞减少和T细胞耗竭，以及独特的TCR特征，可能在DTB发病机制中起关键作用。“CAAMD”基序的减少和TCR克隆型的改变为与该疾病相关的复杂细胞动力学提供了新的见解，可能为靶向免疫干预提供新途径。
