Bile acid restrained T cell activation explains cholestasis aggravated hepatitis B virus infection

Abstract Cholestasis is a common complication of hepatitis B virus (HBV) infection, characterized by increased intrahepatic and plasma bile acid levels. Cholestasis was found negatively associated with hepatitis outcome, however, the exact mechanism by which cholestasis impacts anti‐viral immunity and impedes HBV clearance remains elusive. Here, we found that cholestatic mice are featured with dysfunctional T cells response, as indicated by decreased sub‐population of CD25 + /CD69 + CD4 + and CD8 + cells, while CTLA‐4 + CD4 + and CD8 + subsets were increased. Mechanistically, bile acids disrupt intracellular calcium homeostasis via inhibiting mitochondria calcium uptake and elevating cytoplasmic Ca 2+ concentration, leading to STIM1 and ORAI1 decoupling and impaired store‐operated Ca 2+ entry which is essential for NFAT signaling and T cells activation. Moreover, in a transgenic mouse model of HBV infection, we confirmed that cholestasis compromised both CD4 + and CD8 + T cells activation resulting in poor viral clearance. Collectively, our results suggest that bile acids play pivotal roles in anti‐HBV infection via controlling T cells activation and metabolism and that targeting the regulation of bile acids may be a therapeutic strategy for host‐virus defense.