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

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 Ca²⁺ concentration, leading to STIM1 and ORAI1 decoupling and impaired store-operated Ca²⁺ 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.