Cholangiocytes Modulate CD100 Expression in the Liver and Facilitate Pathogenic T-Helper 17 Cell Differentiation.
In: Gastroenterology (00165085), Jg. 166 (2024-04-01), Heft 4, S. 667-679
academicJournal
Zugriff:
Chronic inflammation surrounding bile ducts contributes to the disease pathogenesis of most cholangiopathies. Poor efficacy of immunosuppression in these conditions suggests biliary-specific pathologic principles. Here we performed biliary niche specific functional interpretation of a causal mutation (CD100 K849T) of primary sclerosing cholangitis (PSC) to understand related pathogenic mechanisms. Biopsy specimens of explanted livers and endoscopy-guided sampling were used to assess the CD100 expression by spatial transcriptomics, immune imaging, and high-dimensional flow cytometry. To model pathogenic cholangiocyte-immune cell interaction, splenocytes from mutation-specific mice were cocultured with cholangiocytes. Pathogenic pathways were pinpointed by RNA sequencing analysis of cocultured cells and cross-validated in patient materials. CD100 is mainly expressed by immune cells in the liver and shows a unique pattern around PSC bile ducts with RNA-level colocalization but poor detection at the protein level. This appears to be due to CD100 cleavage as soluble CD100 is increased. Immunophenotyping suggests biliary-infiltrating T cells as the major source of soluble CD100, which is further supported by reduced surface CD100 on T cells and increased metalloproteinases in cholangiocytes after coculturing. Pathogenic T cells that adhered to cholangiocytes up-regulated genes in the T-helper 17 cell differentiation pathway, and the CD100 mutation boosted this process. Consistently, T-helper 17 cells dominate biliary-resident CD4 T cells in patients. CD100 exerts its functional impact through cholangiocyte-immune cell cross talk and underscores an active, proinflammatory role of cholangiocytes that can be relevant to novel treatment approaches. [Display omitted] A primary biliary cholangitis causal mutation contributes to the pathogenic interaction of immune cells with the cells lining the bile ducts that also have a specific inflammation-driving role. [ABSTRACT FROM AUTHOR]
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Titel: |
Cholangiocytes Modulate CD100 Expression in the Liver and Facilitate Pathogenic T-Helper 17 Cell Differentiation.
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Autor/in / Beteiligte Person: | Jiang, Xiaojun ; Otterdal, Kari ; Chung, Brian K. ; Maucourant, Christopher ; Rønneberg, Jørgen D. ; Zimmer, Christine L. ; Øgaard, Jonas ; Boichuk, Yuliia ; Holm, Sverre ; Geanon, Daniel ; Schneditz, Georg ; Bergquist, Annika ; Björkström, Niklas K. ; Melum, Espen |
Zeitschrift: | Gastroenterology (00165085), Jg. 166 (2024-04-01), Heft 4, S. 667-679 |
Veröffentlichung: | 2024 |
Medientyp: | academicJournal |
ISSN: | 0016-5085 (print) |
DOI: | 10.1053/j.gastro.2023.11.283 |
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