Profibrogenic role of mucosal associated invariant T (MAIT) cells in primary sclerosing cholangitis 2937

Description Background Primary sclerosing cholangitis (PSC) is an immune-mediated liver disease characterized by chronic inflammation and fibrosis of the bile ducts. The primary cells impacted in PSC are bile duct epithelial cells called cholangiocytes. Mucosal associated invariant T (MAIT) cells are enriched in human liver and associated with fibrosis. We hypothesize that cholangiocyte-activated MAIT cells drive fibrosis in PSC. Results Flow cytometry of PSC patient bile duct brushings show that 30% of T cells are MAIT cells, suggesting their co-existence with cholangiocytes within the peri-biliary environment. Re-analysis of single cell RNA sequencing data of PSC patient cholangiocyte organoids reveals upregulation of MR1 gene, indicating their enhanced ability to activate MAIT cells. Proteomics of human MAIT cells identify the expression of multiple profibrotic factors including secreted protein acidic and rich in cysteine (SPARC). Flow cytometry of TCR-activated MAIT cells show a significant and dose-dependent increase in a SPARClow MAIT population, indicating release of SPARC. Re-analysis of Olink proteomics on supernatant of PSC cholangiocyte organoids show IL-17C secretion. IL-17C treatment of TCR-activated MAIT cells result in significant upregulation of SPARC gene. Conclusion MAIT cells secrete profibrogenic mediators and MAIT cell profibrogenicity is enhanced by IL-17C, a novel cytokine released by cholangiocytes in PSC. Funding Sources C-SIG P30DK084567 Topic Categories Mucosal and Regional Immunology (MUC)