OP11 Analysing the T cell receptor beta chain repertoire of 2,800 Inflammatory Bowel Disease patients identifies public T cell responses involved in the pathogenesis of Crohn’s Disease and Ulcerative Colitis and quantifies the impact of surgery and therapy on the immune repertoire of IBD patients

Abstract Background Crohn’s disease (CD) patients have elevated immune responses toward fungal antigens1, altered T cell responses toward gut microbiota2, and dysregulated immune responses toward Epstein-Barr virus3. Nonetheless, a detailed map of public immune responses, e.g. public T cell clonotypes associated with either CD or ulcerative colitis (UC), remains unknown. Additionally, a detailed understanding of the immune responses of different disease sub-phenotypes, e.g. ileal vs. colonic CD, and the influence of different therapies and surgical operations on the immune repertoire of IBD patients remains far from being understood. Methods We analysed the T cell receptor beta (TRB) immune repertoire of 1,890 CD patients and 914 UC patients from the US-based SPARC cohort4. Results By comparing the TRB repertoire of CD to UC patients, we identified 327 and 130 clonotypes associated with CD (Fig. 1A) and UC (Fig. 1B), respectively. Using statistical analyses, we were able to resolve the cognate HLA alleles of these clonotypes with most CD-associated clonotypes restricted to HLA-DRB1*07:01 (Fig. 1C) and UC-associated clonotypes to HLA-DRB1*15:01 alleles (Fig. 1D). CD-associated clonotypes were more expanded in ileal and ileocolonic CD relative to colonic CD and UC patients (Fig. 2A). Similarly, UC-associated clonotypes were expanded only in UC and in neither forms of CD (Fig. 2B), suggesting that different antigens and immune processes are driving CD and UC pathology. The abundance of the CD- and UC-associated clonotypes showed comparable levels in patients with and without colectomy (Fig. 2C-2D). The expansion of CD-associated clonotypes was higher in CD patients treated with Infliximab (Fig. 2E), while the expansion of UC-associated clonotypes was comparable in UC patients treated with or without Infliximab (Fig. 2F). Conclusion By analysing this comprehensive TRB dataset of IBD patients, we identified public clonotypes associated with CD and UC and resolved their cognate HLA alleles. Additionally, we identified clonotype sets associated with different disease sub-phenotypes and quantified the impact of different therapeutic procedures on their expansion. These clonotypes represent promising candidates for novel immunotherapies to treat IBD and understand its aetiology. References 1.Martini GR., Tikhonova E., Rosati E., DeCelie MB., Sievers LK., Tran F., et al. Selection of cross-reactive T cells by commensal and food-derived yeasts drives cytotoxic TH1 cell responses in Crohn’s disease. Nat Med 2023;29(10):2602–14. Doi: 10.1038/s41591-023-02556-5. 2.Uchida AM., Boden EK., James EA., Shows DM., Konecny AJ., Lord JD. Escherichia coli–Specific CD4+ T Cells Have Public T-Cell Receptors and Low Interleukin 10 Production in Crohn’s Disease. Cell Mol Gastroenterol Hepatol 2020;10(3):507–26. Doi: https://doi.org/10.1016/j.jcmgh.2020.04.013. 3.Ebert AC., Harper S., Vestergaard M V., Mitchell W., Jess T., Elmahdi R. Risk of inflammatory bowel disease following hospitalisation with infectious mononucleosis: nationwide cohort study from Denmark. Nat Commun 2024;15(1):8383. Doi: 10.1038/s41467-024-52195-8. 4.Raffals LE., Saha S., Bewtra M., Norris C., Dobes A., Heller C., et al. The Development and Initial Findings of A Study of a Prospective Adult Research Cohort with Inflammatory Bowel Disease (SPARC IBD). Inflamm Bowel Dis 2022;28(2):192–9. Doi: 10.1093/ibd/izab071.