Abstract
INTRODUCTION: The pathogenesis of biliary atresia (BA) is unclear to date and no therapies targeting immune regulatory pathways exist. Here we characterized potent effector liver tissue resident memory CD8(+) T cells (Trm) and monocytic cells in children with advanced BA and an age-matched control group to gain insight into BA pathogenesis and immunologic regulation. METHODS: Liver explants from 18 children with biliary atresia and 10 with metabolic disease and normal histology were analyzed ex vivo by multicolor flow-cytometry and immunohistochemistry. Cytokines and cytotoxic mediators were quantified by intracellular staining and bead-based arrays in culture supernatant. RESULTS: The frequency of CD103(+)CD69(+)CD8(+) Trm cells and CD14(+)CD16(+) monocytes was significantly higher in BA than in the control group. In BA, T cells showed elevated expression of CD103, CD69, CD39 and production of TNF-α and Granzyme-B ex vivo, which could be reproduced in vitro by allowing cell-contact with monocytes. CONCLUSIONS: Cytotoxic CD8(+) Trm cells and intrahepatic monocytes might contribute to tissue destruction in BA. Therapies targeting Trm cells or the TNF-α signaling pathway could be explored to delay progression to cirrhosis in BA.