Abstract Background &amp; Aims 24-NorUrsodeoxycholic acid (NorUDCA) is novel therapy for immune-mediated liver diseases such as primary sclerosing cholangitis (PSC) where dysregulated T cells including CD8 + T cells cause liver immunopathology. We hypothesized that NorUDCA may directly modulate CD8 + T cell effector function thus contributing to its therapeutic efficacy independent of anti-cholestatic effects. Methods NorUDCA effects on CD8 + T cell function in vivo were investigated in a hepatic injury model system induced by excessive CD8 + T cell immune response upon non-cytolytic lymphocytic choriomeningitis virus (LCMV) infection. Mechanistic studies included molecular and biochemical approaches, flow cytometry and metabolic assays in mouse CD8 + T cells in vitro . Mass spectrometry (MS) was used to identify potential targets modulated by NorUDCA in CD8 + T cells. NorUDCA signaling effects observed in murine systems were validated in peripheral T cells from healthy volunteers and PSC patients. Results In vivo NorUDCA ameliorated hepatic injury and systemic inflammation upon LCMV infection. Mechanistically, NorUDCA demonstrated a strong immunomodulatory efficacy in CD8 + T cells affecting lymphoblastogenesis, mTORC1 signaling and glycolysis of CD8 + T cells. With MS, we identified that NorUDCA regulates CD8 + T cells via targeting mTORC1. NorUDCA’s impact on mTORC1 signaling was further confirmed in circulating human CD8 + T cells. Conclusions NorUDCA possesses a yet-unrecognized direct modulatory potency on CD8 + T cells and attenuates excessive CD8 + T cell hepatic immunopathology. These findings may be relevant for treatment of immune-mediated liver diseases such as PSC and beyond.

24-Nor-Ursodeoxycholic acid reshapes immunometabolism in CD8+ T cells and alleviates hepatic inflammation