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

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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.