PD-L1 upregulation by IFN-α/γ-mediated Stat1 suppresses anti-HBV T cell response
PD-L1 upregulation by IFN-α/γ-mediated Stat1 suppresses anti-HBV T cell response
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IFN-α/γ介导的 Stat1 上调 PD-L1 抑制抗 HBV T 细胞反应
DOI：
10.1371/journal.pone.0228302
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发表时间：
2020-07-06
期刊：
影响因子：
3.7
通讯作者：
Meng, Songdong
中科院分区：
文献类型：
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作者：
Liu, LanLan;Hou, Junwei;Meng, Songdong
程序性死亡配体1（PD-L1）最近已被证明是抗病毒免疫的主要障碍，其通过与慢性B肝炎中特异性IFN-γ产生T细胞上的受体程序性死亡1（PD-1）结合。目前，IFN-α被广泛用于治疗B型肝炎病毒（HBV）感染，但其抗病毒效果差异较大，作用机制尚不完全清楚。我们发现IFN-α/γ诱导肝细胞中PD-L1表达显著增加。信号和转录激活因子（Stat 1）被确定为参与IFN-α/γ介导的PD-L1体外和小鼠体内升高的主要转录因子。通过特异性mAb阻断PD-L1/PD-1相互作用极大地增强了gp 96佐剂治疗性疫苗的HBV特异性T细胞活性，并促进HBV转基因小鼠中的HBV清除。我们的研究结果表明IFN-α/γ-Stat 1-PD-L1轴在介导T细胞低反应性和灭活肝脏微环境中的肝脏浸润T细胞中起重要作用。这些数据进一步提高了对增强IFN-α和治疗性疫苗的抗HBV功效的潜在兴趣。
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-gamma producing T cells in chronic hepatitis B. Currently, IFN-alpha 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-alpha/gamma 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-alpha/gamma-mediated PD-L1 elevation bothin vitroand 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-alpha/gamma-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-alpha and therapeutic vaccines.