Abstract Background Primary sclerosing cholangitis (PSC) is an immune-mediated cholangiopathy frequently observed in individuals with IBD, particularly ulcerative colitis. Despite this clinical overlap, PSC-IBD displays distinct disease behaviour compared to classical IBD, suggesting differences in underlying mechanisms. The adaptive immune system records prior antigenic encounters through V(D)J-generated T-cell receptors (TCRs), and sequencing the TCR repertoire across large cohorts enables the statistical identification of disease-associated clonotypes. Methods Most TCR-Seq studies, including our own previous work1, have focused on the more diverse TCR-β chain, leaving the TCR-α (TRA) repertoire comparatively underexplored. Because the TRA chain encodes several unconventional T cell subsets, including MAIT and CAIT cells, it offers a unique opportunity to investigate disease-specific expansions. We analysed TRA repertoires from 154 individuals with PSC, 357 with UC, 228 with CD, 246 symptomatic controls, and 64 population controls from multiple Norwegian cohorts. Results Given the role of the TRA chain in defining unconventional T-cell subsets, we first assessed MAIT and CAIT cell expansion across groups. MAIT cell frequencies were significantly reduced in PSC, UC, and CD compared with both symptomatic and population controls (Fig. 1a). MAIT levels were comparable between the two control groups, while PSC showed the lowest levels among the diseases, indicating a more pronounced depletion. In contrast, CAIT cells displayed strong and preferential expansion in CD, with minimal expansion in UC, PSC, or controls (Fig. 1b), supporting a CD-specific enrichment. Using a hypothesis-free statistical framework following Emerson et al.2, we identified hundreds of TRA clonotypes that significantly differentiated PSC from UC and PSC from CD, demonstrating marked T-cell repertoire distinctions. Conclusion Our results show that individuals with PSC exhibit a TRA repertoire distinct from both UC and CD, supporting the view that PSC is an immunologically separate entity rather than a subtype of IBD. References: 1.ElAbd, H. et al. T and B cell responses against Epstein–Barr virus in primary sclerosing cholangitis. Nat Medhttps://doi.org/10.1038/s41591-025-03692-w (2025) doi:10.1038/s41591-025-03692-w. 2.Emerson, R. O. et al. Immunosequencing identifies signatures of cytomegalovirus exposure history and HLA-mediated effects on the T cell repertoire. Nat Genet 49, 659–665 (2017). Conflict of interest: Elabd, Hesham: I do not have a conflict of interest. Mahdy, Aya: I do not have a conflict of interest. Høivik, Marte: M.L.H. received investigator-initiated research grants from Takeda, Pfizer, Tilllotts, Ferring, and Janssen. Speaker honoraria from Takeda, Tillotts, Ferring, AbbVie, Galapagos, and Meda. She is also on the advisory board of Takeda, Galapagos, MSD, Lilly, and AbbVie. All other co-authors declare no competing interests. Hov, Johannes Espolin Roksund: Personal Fees: Received grants from Biogen. Lecture honoraria from Amgen, Roche, Novartis. Karlsen, Tom Hemming: Personal Fees: Advisory board participation for Intercept, Engetix and Novartis. Franke, Andre: I have no conflicts of interest.
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