Deciphering the Immunological Signature of Inflammatory Bowel Disease Using Large-scale T Cell Receptor Sequencing in a Cohort of Treatment Naïve Patients

• Applicants: Dr. Hesham El Abd; Dr. Sören Franzenburg, Ph.D.
• Subject Area: Immunology
• Term: since 2026
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 579619637

Inflammatory bowel disease (IBD), which includes Crohn’s disease and ulcerative colitis, is a chronic and often debilitating condition that causes inflammation of the digestive tract. Despite major advances in therapy, many patients fail to respond to treatment, relapse after remission, or develop complications. This is largely because the biological mechanisms driving IBD are still not fully understood. In particular, we lack knowledge about which immune cells trigger and sustain intestinal inflammation, and how these cells change during therapy. Each T cell carries a unique receptor, i.e. a unique TCR, that recognizes a specific antigenic target. Using large-scale sequencing technologies, our previous studies have identified hundreds of TCRs, i.e. clonotypes, that appear more frequently in IBD patients than in healthy individuals. Among them, we discovered a new group of cells called Crohn’s-associated invariant T cells (CAIT cells), which are particularly enriched in Crohn’s disease and show features of natural killer T cells. These cells may recognize small-molecule antigens that mimic microbial or drug-derived compounds. However, most large-scale immune profiling studies have been performed on already treated patients, making it difficult to separate disease-related changes from treatment effects. Our current project overcomes this limitation by analyzing samples from treatment-naïve patients collected through the unique IBSEN-III cohort in Norway. This cohort includes blood and tissue samples obtained both before and after treatment, as well as from symptomatic controls without confirmed IBD. By comparing the T cell repertoires between these groups, we aim to distinguish immune signatures caused by disease from those induced by therapy. In the current proposal, we will combine high-throughput T cell receptor sequencing, genetic profiling, and single-cell transcriptomics to (i) identify disease- and treatment-associated T cell clonotypes, (ii) validate and characterize CAIT cells in an independent cohort, (iii) investigate their gene expression and functional diversity, and (iv) develop computational tools for large-scale immune repertoire analysis. The expected outcome is a detailed atlas of the T cell landscape in IBD and a refined list of disease-associated T cells that could serve as biomarkers or therapeutic targets. In the long term, this knowledge will pave the way for personalized immunotherapies, such as targeted removal of disease-associated T cells or vaccines that re-train the immune system, which will ultimately improving treatment outcomes and quality of life for people living with IBD.

• DFG Programme: Research Grants