Intrahepatic virus-specific IL-10-producing CD8 T cells prevent liver damage during chronic hepatitis C virus infection
Intrahepatic virus-specific IL-10-producing CD8 T cells prevent liver damage during chronic hepatitis C virus infection
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DOI：
10.1002/hep.21438
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发表时间：
2006-12-01
期刊：
影响因子：
13.5
通讯作者：
Caillat-Zucman, Sophie
中科院分区：
文献类型：
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作者：
Abel, Michal;Sene, Damien;Caillat-Zucman, Sophie
CD8 T细胞杀死丙型肝炎病毒（HCV）感染的肝细胞被认为有助于慢性HCV感染期间的肝损伤，而HCV非特异性免疫细胞的参与尚不清楚。为了可视化HCV特异性CD8 T细胞与实质靶细胞的空间关系，并检查其与肝细胞坏死和纤维化相关的局部功能活性，我们使用HLA四聚体和共聚焦显微镜对23例慢性HCV感染的HLA- a2或HILA-B7患者的活检进行了观察。肝内四聚体+ （hcv特异性）CD8 T细胞保护免受肝坏死炎症性疾病活动，独立于年龄、性别、病毒载量和病毒基因型。事实上，四聚体+细胞分散在肝脏弱纤维化（低层粘连蛋白表达）和低肝细胞凋亡（TUNEL法）区域，表达IL-10，但不表达IFN γ。相比之下，四聚体阴性CD8 T细胞与活动性坏死性炎症性肝病相关，与层粘连蛋白强表达和肝细胞凋亡共定位，并且比IL-10更频繁地表达IFN γ。总体而言，含有hcv特异性CD8 T细胞的肝脏区域往往比仅含有特异性不明的炎症细胞的肝脏区域更健康。总之，hcv特异性产生il -10的CD8 T细胞虽然没有细胞毒性，也不能控制病毒复制，但可以减轻由旁观者T细胞介导的肝细胞坏死、肝纤维化和炎症，因此可能代表抗原诱导的调节性CD8 T细胞。治疗性调节特异性和旁观者CD8 T细胞之间的肝内平衡可能对慢性丙型肝炎患者有益。
CD8 T cell killing of hepatitis C virus (HCV)-infected hepatocytes is thought to contribute to liver damage during chronic HCV infection, whereas the participation of HCV-nonspecific immune cells is unclear. To visualize the spatial relationship of HCV-specific CD8 T cells with parenchymal target cells, and to examine their local functional activity in relation to hepatocellular necrosis and fibrosis, we used HLA tetramers and confocal microscopy in biopsies from 23 HLA-A2 or HILA-B7 patients with chronic HCV infection. Intrahepatic tetramer+ (HCV-specific) CD8 T cells protected from hepatic necroinflammatory disease activity, independently of age, gender, viral load, and viral genotype. Indeed, tetramer+ cells were scattered in the liver within regions of weak fibrosis (low laminin expression) and low hepatocellular apoptosis (TUNEL method), and expressed IL-10 but not IFN gamma. By contrast, tetramer-negative CD8 T cells were associated with active necroinflammatory liver disease, colocalized with strong laminin expression and hepatocellular apoptosis, and expressed more frequently IFN gamma than IL-10. Overall, liver regions harboring HCV-specific CD8 T cells tended to be healthier than areas containing only inflammatory cells of undefined specificity. In conclusion, HCV-specific IL-10-producing CD8 T cells, although not cytotoxic and unable to control viral replication, can attenuate hepatocellular necrosis, liver fibrosis, and inflammation mediated by bystander T cells, and may thus represent antigen-induced regulatory CD8 T cells. Therapeutic modulation of the intrahepatic balance between specific and bystander CD8 T cells might be beneficial in patients with chronic hepatitis C.