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标题: 乙型肝炎病毒感染期间CD8 T细胞表位呈递的时空差异 [打印本页]

作者: StephenW    时间: 2019-2-6 02:28     标题: 乙型肝炎病毒感染期间CD8 T细胞表位呈递的时空差异

Spatiotemporal Differences in Presentation of CD8 T Cell Epitopes during Hepatitis B Virus Infection
Atefeh Khakpoor, Yi Ni, Antony Chen, Zi Zong Ho, Vincent Oei, Ninghan Yang, Reshmi Giri, Jia Xin Chow, Anthony T. Tan, Patrick T. Kennedy, Mala Maini, Stephan Urban, Antonio Bertoletti
J.-H. James Ou, Editor
DOI: 10.1128/JVI.01457-18

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ABSTRACT

Distinct populations of hepatocytes infected with hepatitis B virus (HBV) or only harboring HBV DNA integrations coexist within an HBV chronically infected liver. These hepatocytes express HBV antigens at different levels and with different intracellular localizations, but it is not known whether this heterogeneity of viral antigen expression could result in an uneven hepatic presentation of distinct HBV epitopes/HLA class I complexes triggering different levels of activation of HBV-specific CD8+ T cells. Using antibodies specific to two distinct HLA-A*02:01/HBV epitope complexes of HBV nucleocapsid and envelope proteins, we mapped their topological distributions in liver biopsy specimens of two anti-hepatitis B e antigen-positive (HBe+) chronic HBV (CHB) patients. We demonstrated that the core and envelope CD8+ T cell epitopes were not uniformly distributed in the liver parenchyma but preferentially located in distinct and sometimes mutually exclusive hepatic zones. The efficiency of HBV epitope presentation was then tested in vitro utilizing HLA-A*02:01/HBV epitope-specific antibodies and the corresponding CD8+ T cells in primary human hepatocyte and hepatoma cell lines either infected with HBV or harboring HBV DNA integration. We confirmed the existence of a marked variability in the efficiency of HLA class I/HBV epitope presentation among the different targets that was influenced by the presence of gamma interferon (IFN-γ) and availability of newly translated viral antigens. In conclusion, HBV antigen presentation can be heterogeneous within an HBV-infected liver. As a consequence, CD8+ T cells of different HBV specificities might have different antiviral efficacies.

IMPORTANCE The inability of patients with chronic HBV infection to clear HBV is associated with defective HBV-specific CD8+ T cells. Hence, the majority of immunotherapy developments focus on HBV-specific T cell function restoration. However, knowledge of whether distinct HBV-specific T cells can equally target all the HBV-infected hepatocytes of a chronically infected liver is lacking. In this work, analysis of CHB patient liver parenchyma and in vitro HBV infection models shows a nonuniform distribution of HBV CD8+ T cell epitopes that is influenced by the presence of IFN-γ and availability of newly translated viral antigens. These results suggest that CD8+ T cells recognizing different HBV epitopes can be necessary for efficient immune therapeutic control of chronic HBV infection.

    Copyright © 2019 Khakpoor et al.
作者: StephenW    时间: 2019-2-6 02:28

乙型肝炎病毒感染期间CD8 T细胞表位呈递的时空差异
Atefeh Khakpoor,Yi Ni,Antony Chen,Zi Zong Ho,Vincent Oei,Ninghan Yang,Reshmi Giri,Jia Xin Chow,Anthony T. Tan,Patrick T. Kennedy,Mala Maini,Stephan Urban,Antonio Bertoletti
J.-H. James Ou,编辑
DOI:10.1128 / JVI.01457-18

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抽象

感染乙型肝炎病毒(HBV)或仅携带HBV DNA整合的肝细胞的不同群体在HBV慢性感染的肝脏内共存。这些肝细胞表达不同水平和不同细胞内定位的HBV抗原,但尚不清楚这种病毒抗原表达的异质性是否会导致不同HBV表位/ HLA I类复合物的不均匀肝脏表现,从而引发不同程度的HBV活化。特异性CD8 + T细胞。使用特异于HBV核衣壳和包膜蛋白的两种不同HLA-A * 02:01 / HBV表位复合物的抗体,我们在两种抗乙型肝炎e抗原阳性(HBe +)慢性HBV(CHB)的肝活检标本中绘制了它们的拓扑分布图。 ) 耐心。我们证明了核心和包膜CD8 + T细胞表位在肝实质中不是均匀分布的,而是优先位于不同的,有时相互排斥的肝区。然后在体外利用HLA-A * 02:01 / HBV表位特异性抗体和原代人肝细胞和肝细胞瘤细胞系中相应的CD8 + T细胞测试HBV表位呈递的效率,所述细胞系感染HBV或携带HBV DNA整合。我们证实了受γ干扰素(IFN-γ)的存在和新翻译的病毒抗原的可用性影响的不同靶标中HLA I类/ HBV表位呈递效率的显着变化。总之,HBV抗原呈递在HBV感染的肝脏中可以是异质的。因此,不同HBV特异性的CD8 + T细胞可能具有不同的抗病毒效力。

重要性慢性HBV感染患者无法清除HBV与HBV特异性CD8 + T细胞缺陷有关。因此,大多数免疫治疗开发集中于HBV特异性T细胞功能恢复。然而,缺乏对不同HBV特异性T细胞是否能够同等靶向慢性感染肝脏的所有HBV感染的肝细胞的了解。在这项工作中,CHB患者肝实质和体外HBV感染模型的分析显示HBV CD8 + T细胞表位的不均匀分布受IFN-γ的存在和新翻译的病毒抗原的可用性的影响。这些结果表明识别不同HBV表位的CD8 + T细胞可能是慢性HBV感染的有效免疫治疗控制所必需的。

    版权所有©2019 Khakpoor等。
作者: StephenW    时间: 2019-2-6 02:29

https://jvi.asm.org/content/93/4/e01457-18.full




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