Institute of Hepatology, University College London, London, U.K.
J Immunol. 2010 Jan 1;184(1):287-95. doi: 10.4049/jimmunol.0902761. Epub 2009 Nov 30.
Resolution of hepatitis B virus (HBV) infection was believed to be attributed to the cytotoxic T cell-mediated killing of infected hepatocytes. However, studies in HBV transgenic mice and HBV-infected chimpanzees revealed that T cell control of HBV replication also involves cytokine-mediated noncytolytic mechanisms. The relative role of cytolytic and noncytolytic functions of virus-specific CD8(+) T cells during interaction with HBV-producing hepatocytes is not well understood. By using HLA-A2 matched effector cells (CD8(+) T cell line or clone) and target cells supporting full HBV replication, we demonstrate that virus-specific CD8(+) T cells can inhibit HBV replication in HBV-producing hepatocytes with minimal cell lysis. Although CD8(+) T cells kill a fraction of infected cells, this effect is minimal, and most of the viral inhibition is mediated by noncytolytic mechanisms. CD8(+) T cells produce an array of cytokines, among which IFN-gamma and TNF-alpha are responsible for HBV inactivation in the target cells. Blockade of IFN-gamma and TNF-alpha abrogated the noncytolytic inhibition of HBV, indicating that these two cytokines mediate the control of HBV by noncytolytic mechanisms. Furthermore, treatment of the HBV-producing hepatocytes with rIFN-gamma and rTNF-alpha resulted in an efficient suppression of viral replication without cytotoxicity. In contrast, coculture of the same target cells with activated HLA-mismatched mitogen-activated lymphomononuclear cells caused a marked cytolytic effect and was less effective in HBV control. These results provide direct evidence that virus-specific CD8(+) T cells efficiently control HBV replication by noncytolytic mechanisms, and this effect is mediated by IFN-gamma and TNF-alpha.
乙型肝炎病毒 (HBV) 感染的清除被认为归因于细胞毒性 T 细胞介导的感染肝细胞的杀伤。然而，在乙型肝炎病毒转基因小鼠和乙型肝炎病毒感染的黑猩猩中的研究表明，T 细胞对乙型肝炎病毒复制的控制还涉及细胞因子介导的非细胞溶解机制。在与产生乙型肝炎病毒的肝细胞相互作用时，病毒特异性 CD8(+) T 细胞的细胞溶解和非细胞溶解功能的相对作用尚不清楚。通过使用 HLA-A2 匹配的效应细胞 (CD8(+) T 细胞系或克隆) 和支持完全乙型肝炎病毒复制的靶细胞，我们证明病毒特异性 CD8(+) T 细胞可以在最小细胞裂解的情况下抑制产生乙型肝炎病毒的肝细胞中的乙型肝炎病毒复制。尽管 CD8(+) T 细胞杀伤一部分感染细胞，但这种效应很小，并且大多数病毒抑制是由非细胞溶解机制介导的。CD8(+) T 细胞产生一系列细胞因子，其中 IFN-γ和 TNF-α负责靶细胞中乙型肝炎病毒的失活。IFN-γ和 TNF-α 的阻断消除了乙型肝炎病毒的非细胞溶解抑制，表明这两种细胞因子通过非细胞溶解机制介导乙型肝炎病毒的控制。此外，用 rIFN-γ和 rTNF-α 处理产生乙型肝炎病毒的肝细胞导致在没有细胞毒性的情况下有效抑制病毒复制。相比之下，相同靶细胞与激活的 HLA 错配有丝分裂原激活的淋巴母细胞共培养导致明显的细胞溶解效应，并且在乙型肝炎病毒控制方面效果较差。这些结果提供了直接证据，表明病毒特异性 CD8(+) T 细胞通过非细胞溶解机制有效地控制乙型肝炎病毒复制，并且这种效应是由 IFN-γ和 TNF-α介导的。
