Temporal assessment of spatial and single-cell transcriptomes identifies CD226-NECTIN2 T cell-cholangiocyte interaction in bile duct inflammation.

Authors

Markus S Jördens, Kathrine S Nordhus, Jonas Øgaard, Enya Amundsen-Isaksen, Oda H Ramberg, Jeremy Yeoh, Kristian Holm, Xiaojun Jiang, Tom Luedde, Tom H Karlsen, Brian K Chung, Espen Melum

Published in

Journal of hepatology. Oct 05, 2026. Epub Oct 05, 2026.

Abstract

Primary sclerosing cholangitis (PSC) and primary biliary cholangitis (PBC) are inflammatory bile duct disorders affecting mostly young adults that often lead to liver cirrhosis and cancer. Especially for PSC, pathogenic mechanisms remain unclear and treatment options are lacking. To better understand biliary disease processes in bile duct inflammation, we analyzed livers of NOD.c3c4 mice by spatial and single-cell (scRNA-seq) transcriptomics, identifying key cell types, interactions and potential changes over time that were validated in human liver explants.
Livers of 10, 20 and 40-week-old male NOD.c3c4 mice were used for spatial transcriptomics and scRNA-seq. Differentially-expressed genes at different time points were analyzed using the CellphoneDB database with a focus on T cell-related interactions. CD226-NECTIN2 interaction was validated using co-culture experiments and antibody treatment in NOD.c3c4 mice. CD226-NECTIN2 in PSC, PBC and alcohol-related liver disease (ALD) explants was analyzed by spatial transcriptomics and immunofluorescence.
Spatial transcriptomics consistently distinguished inflamed and non-inflamed liver areas in NOD.c3c4 mice at different ages. When combined with scRNA-seq enriched for immune cells and cholangiocytes, key inflammatory cell types were localized to biliary structures. Using differentially-expressed genes and a curated overview of biologically-validated interactions (CellphoneDB), the CD226-NECTIN2 T cell-cholangiocyte interaction was discovered. Knock-down of Nectin2 in vitro and anti-CD226 blocking in NOD.c3c4 mice specifically reduced T cell activation and diseased human liver showed consistent CD226-NECTIN2 co-localization at inflamed bile ducts.
By combining spatial transcriptomics and scRNA-seq in NOD.c3c4 mice, we generated a pipeline for in-depth identification of potential disease relevant genes and interaction partners. The T cell-cholangiocyte interaction CD226-NECTIN2 was identified, functionally validated and detected in human disease highlighting this interaction as a possible future treatment target.
PSC is an intractable immune-mediated cholestatic liver disease that mainly affects young people and has a significant impact on families and the healthcare system due to treatment costs and sick leave. Our study aimed to find new ways of understanding PSC and highlight potential treatment targets by first identifying disease-relevant cell interactions in a mouse model, followed by confirmation in human PSC livers.

PMID:
42833310
Bibliographic data and abstract were imported from PubMed on 06 Oct 2026.

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