Key Laboratory of Infection and Immunity, Institute of Biophysics, Chinese Academy of Sciences, Beijing 100101, China.
J Immunol. 2012 Jan 15;188(2):824-31. doi: 10.4049/jimmunol.1102205. Epub 2011 Dec 7.
The granule exocytosis pathway of cytotoxic lymphocytes plays critical roles in eradication of intracellular viruses. However, how hepatitis B virus (HBV) is cleared has not been defined. To clarify immune mechanisms underlying inhibition of the HBV replication, the relationship between granzyme H (GzmH) and HBV clearance was investigated. In this study, we found that the granule exocytosis pathway can inhibit HBV replication without induction of cytolysis of the infected cells. GzmH is essential for HBV eradication. The HBx protein (HBx), required for the replication of HBV, is cleaved at Met(79) by GzmH. GzmH inhibitor can abolish GzmH- and lymphokine-activated killer cell-mediated HBx degradation and HBV clearance. An HBx-deficient HBV is resistant to GzmH- and lymphokine-activated killer cell-mediated viral clearance. Adoptive transfer of GzmH-overexpressing NK cells into HBV carrier mice facilitates in vivo HBV eradication. Importantly, low GzmH expression in cytotoxic lymphocytes of individuals is susceptible to HBV infection and hepatocellular carcinoma. These results indicate that GzmH might be detected as a potential parameter for diagnosis of HBV infection and hepatocellular carcinoma.
细胞毒性淋巴细胞的颗粒外排途径在清除细胞内病毒方面发挥着关键作用。然而，HBV（乙型肝炎病毒）是如何被清除的尚未确定。为了阐明抑制 HBV 复制的免疫机制，研究了颗粒酶 H（GzmH）与 HBV 清除之间的关系。在这项研究中，我们发现颗粒外排途径可以在不诱导感染细胞裂解的情况下抑制 HBV 复制。GzmH 对于 HBV 的清除是必不可少的。HBx 蛋白（HBx）是 HBV 复制所必需的，可被 GzmH 在 Met(79)处切割。GzmH 抑制剂可消除 GzmH 和淋巴因子激活的杀伤细胞介导的 HBx 降解和 HBV 清除。缺乏 HBx 的 HBV 可抵抗 GzmH 和淋巴因子激活的杀伤细胞介导的病毒清除。将过表达 GzmH 的 NK 细胞过继转移到 HBV 携带者小鼠体内可促进体内 HBV 清除。重要的是，个体细胞毒性淋巴细胞中 GzmH 的低表达易发生 HBV 感染和肝细胞癌。这些结果表明，GzmH 可作为诊断 HBV 感染和肝细胞癌的潜在参数进行检测。
