胆汁淤积
乙型肝炎病毒
胆汁酸
NFAT公司
免疫学
T细胞
生物
化学
病毒
免疫系统
内分泌学
内科学
医学
钙调神经磷酸酶
移植
作者
Chujie Ding,Hong Yu,Yuan Che,Tianyu He,Yun Wang,Shule Zhang,Jiawei Wu,Wanfeng Xu,Jingyi Hou,Haiping Hao,Lijuan Cao
标识
DOI:10.1096/fj.202200332r
摘要
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.
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