Identification of disease-associated traits and clonotypes in the T-cell receptor repertoire of monozygotic twins affected by inflammatory bowel diseases. TCR repertoire in IBD twins

Background and aims: Intestinal inflammation in inflammatory bowel diseases (IBD) is thought to be T cell mediated and therefore dependent on the interaction between the T-cell receptor (TCR) and human leukocyte antigen (HLA) proteins expressed on antigen presenting cells. The collection of all TCRs in one individual, known as the TCR repertoire, is characterized by enormous diversity and inter-individual variability. It was shown that healthy monozygotic (MZ) twins are more similar in their TCR repertoire than unrelated individuals. Therefore, MZ twins concordant or discordant for IBD may be useful to identify disease-related and non-genetic factors in the TCR repertoire that could potentially be used as disease biomarkers. Methods and results: Employing unique molecular barcoding that can distinguish between PCR artefacts and true sequence variation, we performed deep TCRα and TCRβ repertoire profiling of the peripheral blood of 28 MZ twin pairs from Denmark and Germany, 24 of which were discordant and 4 concordant for IBD. We observed disease-associated traits such as sharing, diversity and abundance of specific clonotypes in the TCR repertoire of IBD patients, and particularly in patients with active disease, compared to their healthy twins. Conclusions: Our findings identified TCR repertoire features specific for IBD and major differences in the circulating lymphocytes of patients with active disease. These findings are a first step towards the application of TCR repertoire analyses as a valuable tool to characterize inflammatory bowel diseases and to identify potential biomarkers and true disease causes.

研究背景与目的：炎症性肠病（IBD）的肠道炎症被认为由T细胞介导，因此依赖于T细胞受体（TCR）与抗原呈递细胞表面表达的人类白细胞抗原（HLA）蛋白之间的相互作用。单个个体内所有TCR的集合被称为T细胞受体库（TCR repertoire），其具有极高的多样性与个体间差异。已有研究证实，健康同卵（MZ）双胞胎的T细胞受体库相较于无关个体更为相似。因此，患有或未患有IBD的同卵双胞胎（包括疾病一致型与不一致型双胞胎）可用于识别T细胞受体库中与疾病相关及非遗传的因素，这些因素有望作为疾病生物标志物。

研究方法与结果：本研究采用可区分聚合酶链式反应（PCR）扩增伪影与真实序列变异的独特分子条形码技术，对来自丹麦与德国的28对同卵双胞胎的外周血进行了深度TCRα链与TCRβ链受体库测序分析，其中24对为IBD不一致型双胞胎，4对为一致型双胞胎。相较于其健康双胞胎同胞，我们在IBD患者，尤其是处于疾病活动期的患者的T细胞受体库中，观察到了与疾病相关的特征，包括特定T细胞克隆型的共享情况、多样性及丰度变化。

研究结论：本研究鉴定出了炎症性肠病特异性的T细胞受体库特征，以及活动期IBD患者循环淋巴细胞的显著差异。上述发现为将T细胞受体库分析作为表征炎症性肠病的有效工具、识别潜在疾病生物标志物及明确疾病真正病因迈出了第一步。