Analysis of T cell receptor heterogeneity in healthy individuals and inflammatory bowel disease and its interaction with microbial composition

炎症性肠道疾病（IBD）是一种免疫介导的疾病。IBD的特征是炎症和组织损伤，从而建立恶性循环，导致慢性疾病。CD 4 + T细胞是这种免疫反应的特征。同时，IBD患者显示出明显的肠道生态失调。IBD期间微生物组变化与T细胞活化之间的联系尚未解决。然而，单细胞RNA测序允许测量每个细胞的转录组和T细胞受体。这允许无偏检测共享相同T细胞受体（克隆型）和细胞异质性的细胞。我的目标是研究不同器官的器官供体中的健康T细胞，以构建预期克隆型的图谱，并开发一个检测意外克隆型的框架。我们将根据其同源抗原对这些克隆型进行分层，以解释检测到的异质性。在第二步中，我们试图使用这些数据作为基础来研究IBD期间微生物变化的作用。值得注意的是，甲硝唑的抗生素治疗在一些IBD患者中是有效的，并且例如在克罗恩病的手术中或在结肠袋炎期间使用。我们假设抗生素治疗将导致微生物群特异性T细胞的变化，从而使我们能够识别潜在的疾病驱动微生物群- T细胞相互作用。为此，将在抗生素治疗前后2个月对IBD患者进行研究，并对结肠镜活检进行测序。我们的目标是解开T辅助细胞的变化，这可能使抗原特异性T细胞的靶向治疗在未来。

Inflammatory bowel disease (IBD) is one type of immune-mediated disease. IBD is characterized by inflammation and tissue damage, thereby establishing a vicious circle leading to a chronic disease. CD4+ T cells are characteristic of this immune response. In parallel, patients with IBD show a marked intestinal dysbiosis. The link between changes in microbiome and T-cell activation during IBD is unsolved. However, single-cell RNA sequencing allows measurement of the transcriptome and T-cell receptor for each individual cell. This allows unbiased detection of cells that share the same T-cell receptor (clonotype) and cellular heterogeneity. I aim to study healthy T cells in organ donors across various organs to construct an atlas of expected clonotypes and develop a framework that detects unexpected clonotypes. We will stratify these clonotypes based on their cognate antigen to explain the detected heterogeneity. In a second step we seek to use these data as basis to study the role of microbial changes during IBD. Of note, antibiotic treatment with metronidazole is effective in some IBD patients and is for example used upon operation in Crohn’s disease, or during pouchitis. We hypothesize that the antibiotic treatment will cause changes in microbiota-specific T cells, thus enabling us to identify potential disease driving microbiota – T cell interactions. To that end patients with IBD will be studied before and after 2 months of antibiotic treatment and biopsies from colonoscopy will be sequenced. Our aim is to unravel changes in T-helper cells that might allow targeted therapy of antigen-specific T cells in the future.