CAS Key Laboratory of Pathogenic Microbiology and Immunology, Center for Biosafety Mega-Science, Chinese Academy of Sciences (CAS), Institute of Microbiology, Beijing, China.
Institutes of Physical Science and Information Technology, Anhui University, Hefei, China.
PLoS One. 2020 Jul 6;15(7):e0228302. doi: 10.1371/journal.pone.0228302. eCollection 2020.
Programmed death ligand 1 (PD-L1) has been recently shown to be a major obstacle to antiviral immunity by binding to its receptor programmed death 1 (PD-1) on specific IFN-γ producing T cells in chronic hepatitis B. Currently, IFN-α is widely used to treat hepatitis B virus (HBV) infection, but its antiviral effect vary greatly and the mechanism is not totally clear. We found that IFN-α/γ induced a marked increase of PD-L1 expression in hepatocytes. Signal and activators of transcription (Stat1) was then identified as a major transcription factor involved in IFN-α/γ-mediated PD-L1 elevation both in vitro and in mice. Blockage of the PD-L1/PD-1 interaction by a specific mAb greatly enhanced HBV-specific T cell activity by the gp96 adjuvanted therapeutic vaccine, and promoted HBV clearance in HBV transgenic mice. Our results demonstrate the IFN-α/γ-Stat1-PD-L1 axis plays an important role in mediating T cell hyporesponsiveness and inactivating liver-infiltrating T cells in the hepatic microenvironment. These data raise further potential interest in enhancing the anti-HBV efficacy of IFN-α and therapeutic vaccines.
程序性死亡配体 1（PD-L1）最近被证明是慢性乙型肝炎中特异性 IFN-γ产生 T 细胞上与其受体程序性死亡受体 1（PD-1）结合的抗病毒免疫的主要障碍。目前，IFN-α 被广泛用于治疗乙型肝炎病毒（HBV）感染，但它的抗病毒作用差异很大，其机制尚不完全清楚。我们发现 IFN-α/γ 诱导肝细胞中 PD-L1 表达明显增加。然后发现信号转导和转录激活因子（Stat1）是 IFN-α/γ 介导 PD-L1 上调的主要转录因子，无论是在体外还是在小鼠中都是如此。通过特异性 mAb 阻断 PD-L1/PD-1 相互作用，gp96 佐剂治疗性疫苗大大增强了 HBV 特异性 T 细胞的活性，并促进了乙型肝炎转基因小鼠的 HBV 清除。我们的结果表明 IFN-α/γ-Stat1-PD-L1 轴在介导 T 细胞低反应性和失活肝内浸润 T 细胞方面发挥重要作用。这些数据进一步提高了增强 IFN-α 和治疗性疫苗抗 HBV 疗效的潜力。
