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.

Automated summary

Cholestasis, a common complication of hepatitis B virus infection, has been found to negatively impact T cells response and hinder viral clearance. Bile acids disrupt calcium homeostasis, impairing T cells activation and signaling. Targeting bile acid regulation may be a therapeutic strategy for host-virus defense.