Primary sclerosing cholangitis (PSC), characterized by biliary tract inflammation and fibrosis is a chronic cholestatic immune mediated disease without any proven effective therapies which often lead to end stage liver disease. Interleukin-17 (IL-17)C is a functionally distinct member of the IL-17 family of cytokines that acts through its receptors IL- 17RE and IL-17RA to promote innate defense in epithelial cells and autoinflammatory disorders (1). The liver is particularly enriched with unconventional T cells, a subgroup of T cells that are characterized by innate immune cell properties. Mucosal-associated invariant T (MAIT) cells are the most abundant unconventional T cells in the human liver. The antigen presenting molecule for MAIT cells, major histocompatibility complex-I molecule (MR1) has been shown to be expressed on cholangiocytes, which are biliary epithelial cells suggesting that cholangiocytes harbor the ability to crosstalk with MAIT cells (2). Our central hypothesis is that MAIT cell and cholangiocytes crosstalk utilizing the IL-17C/IL-17RE axis. To this end, we have made the following observations: (a) cholangiocyte derived organoids from patients with PSC produce IL-17C (b) single cell analysis of patient derived cholangiocyte organoids display an increased expression of MR-1 in the setting of PSC compared to control specimens (c) secondary analysis of human bulk-RNA sequencing datasets reveal IL-17RE expression is enriched in MAIT cells compared to conventional T cells (d) analysis of published single-cell RNA sequencing data on human intrahepatic T cells from 11 PSC liver samples (3) demonstrate that IL-17RE expression is predominantly concentrated on the MAIT cell cluster. Results of this study will deepen our understanding of MAIT cell mediated pathogenesis of chronic liver disease. Importantly, mechanisms deciphered in this project have the potential to introduce IL-17C as a novel therapeutic target to treat PSC.