State Key Laboratory of Nature Medicines, Key Laboratory of Drug Metabolism and Pharmacokinetic, China Pharmaceutical University, Nanjing, China.
FASEB J. 2022 Sep;36(9):e22468. doi: 10.1096/fj.202200332R.
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 concentration, leading to STIM1 and ORAI1 decoupling and impaired store-operated Ca 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.
胆汁淤积是乙型肝炎病毒（HBV）感染的常见并发症，其特征是肝内和血浆胆汁酸水平升高。胆汁淤积与肝炎结局呈负相关，然而，胆汁淤积影响抗病毒免疫并阻碍 HBV 清除的确切机制仍不清楚。在这里，我们发现胆汁淤积小鼠的 T 细胞反应出现功能障碍，表现为 CD25/CD69 CD4 和 CD8 细胞亚群减少，而 CTLA-4 CD4 和 CD8 亚群增加。在机制上，胆汁酸通过抑制线粒体钙摄取和增加细胞质 Ca 浓度来破坏细胞内钙稳态，导致 STIM1 和 ORAI1 解偶联以及储存操作 Ca 进入受损，这对于 NFAT 信号和 T 细胞激活是必不可少的。此外，在 HBV 感染的转基因小鼠模型中，我们证实胆汁淤积会损害 CD4 和 CD8 T 细胞的激活，导致病毒清除不良。总之，我们的研究结果表明，胆汁酸通过控制 T 细胞激活和代谢在抗 HBV 感染中发挥关键作用，靶向调节胆汁酸可能是宿主-病毒防御的一种治疗策略。
