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Cholangiocytes modulate CD100 expression in the liver and facilitate pathogenic Th17 differentiation.

Gastroenterology 2023 November 22
BACKGROUND & AIMS: Chronic inflammation surrounding bile ducts contributes to the disease pathogenesis of most cholangiopathies. Poor efficacy of immunosuppression in these conditions suggests biliary-specific pathological principles. Here we perform biliary niche specific functional interpretation of a causal mutation (CD100 K849T) of primary sclerosing cholangitis (PSC) to understand related pathogenic mechanisms.

METHODS: Biopsies 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 co-cultured with cholangiocytes. Pathogenic pathways were pinpointed by RNA sequencing analysis of co-cultured cells and cross-validated in patient materials.

RESULTS: CD100 is mainly expressed by immune cells in the liver and shows a unique pattern around PSC bile ducts with RNA-level co-localization but poor detection at the protein-level. This appears to be due to CD100 cleavage as soluble CD100 (sCD100) is increased. Immunophenotyping suggests biliary-infiltrating T cells as the major source of sCD100, which is further supported by reduced surface CD100 on T cells and increased metalloproteinases in cholangiocytes after co-culturing. Pathogenic T cells that adhered to cholangiocytes upregulated genes in T-helper 17 (Th17) differentiation pathway, and the CD100 mutation boosted this process. Consistently, Th17 cells dominate biliary-resident CD4 T cells in patients.

CONCLUSIONS: CD100 exerts its functional impact through cholangiocyte-immune cell crosstalk and underscores an active, proinflammatory role of cholangiocytes that can be relevant to novel treatment approaches.

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