Nakakuki Natsuko, Maekawa Shinya, Takano Shinichi, Osawa Leona, Komiyama Yasuyuki, Takada Hitomi, Muraoka Masaru, Suzuki Yuichiro, Sato Mitsuaki, Enomoto Nobuyuki
Department of Gastroenterology and Hepatology, Faculty of Medicine, University of Yamanashi, Chuo, Yamanashi, Japan.
J Gastroenterol Hepatol. 2025 Feb;40(2):537-547. doi: 10.1111/jgh.16835. Epub 2024 Dec 2.
The T cell receptor (TCR) can recognize a vast number of antigens and is closely associated with the pathogenesis of various diseases including autoimmune diseases and malignancies. However, the clinical significance of the TCR repertoire and its post-treatment changes remain unclear in liver diseases.
We performed next-generation sequencing (NGS)-based TCR analysis using DNA obtained from peripheral blood mononuclear cells (PBMCs) of healthy donors (HD, n = 5), primary biliary cholangitis (PBC, n = 5), autoimmune hepatitis (AIH, n = 5), and hepatocellular carcinoma (HCC, n = 5) and evaluated the changes after treatment.
Baseline TCR repertoire analysis demonstrated that TCR clonotype usage is restricted and diversity is low in all three disease groups (PBC, AIH, and HCC), particularly in PBC and AIH compared to HD (p < 0.05). Following treatment, clonotype usage and diversity did not change significantly, except in AIH, where diversity decreased further (p < 0.05 for clone Shannon diversity and clone evenness). Disease-specific usage of TCR beta genes and specific changes after therapy were observed in all groups. Analysis of clonotypes shared with other individuals (public clonotypes) revealed that nine public clonotypes in PBC, eight in AIH, and eight in HCC disappeared after treatment. Motif analysis identified one characteristic motif (NQPQH) in PBC.
The diversity of the TCR repertoire, TCR beta chain usage, clonotypes, and motifs and their post-treatment changes are disease-specific in each liver disease, indicating that further TCR repertoire studies are needed to accelerate the understanding of liver disease pathogenesis from an immunological perspective.
T细胞受体（TCR）能够识别大量抗原，且与包括自身免疫性疾病和恶性肿瘤在内的多种疾病的发病机制密切相关。然而，TCR库在肝脏疾病中的临床意义及其治疗后的变化仍不明确。
我们使用从健康供体（HD，n = 5）、原发性胆汁性胆管炎（PBC，n = 5）、自身免疫性肝炎（AIH，n = 5）和肝细胞癌（HCC，n = 5）的外周血单个核细胞（PBMC）中获取的DNA，进行基于二代测序（NGS）的TCR分析，并评估治疗后的变化。
基线TCR库分析表明，在所有三个疾病组（PBC、AIH和HCC）中，TCR克隆型的使用受限且多样性较低，与HD相比，在PBC和AIH中尤为明显（p < 0.05）。治疗后，除AIH外，克隆型的使用和多样性没有显著变化，在AIH中多样性进一步降低（克隆香农多样性和克隆均匀度p < 0.05）。在所有组中均观察到TCRβ基因的疾病特异性使用情况以及治疗后的特定变化。对与其他个体共享的克隆型（公共克隆型）分析显示，PBC中有9个公共克隆型、AIH中有8个公共克隆型、HCC中有8个公共克隆型在治疗后消失。基序分析在PBC中鉴定出一个特征基序（NQPQH）。
TCR库的多样性、TCRβ链的使用、克隆型和基序及其治疗后的变化在每种肝脏疾病中都具有疾病特异性，这表明需要进一步进行TCR库研究，以从免疫学角度加速对肝脏疾病发病机制的理解。
