男性低乙型肝炎病毒特异性T细胞反应与鼠模型中的高调节性T

StephenW

Low hepatitis B virus–specific T-cell response in males correlates with high regulatory T-cell numbers in murine models
Authors

    First published: 26 May 2017Full publication history
    DOI: 10.1002/hep.29155  View/save citation
    Cited by (CrossRef): 0 articles Check for updates

    Funding Information

    Potential conflict of interest: Nothing to report.

    Supported by the Deutsche Forschungsgemeinschaft (TRR60 and RTG1949).

    A.D. Kosinska's and M. Roggendorf's current address is: Institute of Virology, Technische Universität/Helmholtz Zentrum München, Munich, Germany. L. Pishraft-Sabet's current address is: Razi Vaccine and Serum Research Institute, Agricultural Research, Education and Extension Organization (AREEO), Karaj, Iran.

Abstract

Hepatitis B virus (HBV) infection shows significant gender-related differences in pathogenesis, disease progression, and development of hepatocellular carcinoma. The gender-associated differences in HBV replication and viral protein levels may be associated with distinct HBV-specific immune responses in the host. In the present study, we examined the impact of gender on HBV-specific immune responses in two different mouse models representing transient and persistent hepadnaviral infection; hydrodynamic injection with the HBV genome mimicked acute HBV infection, whereas the efficacy of therapeutic vaccination was studied in the woodchuck hepatitis virus transgenic mouse model. Consistent with previous reports, significantly higher HBV DNA and protein levels were detected in male compared to female mice. Although hydrodynamic injection with the HBV genome resulted in similar numbers of intrahepatic HBV-specific cluster of differentiation 8–positive (CD8+) T cells, their functionality was significantly reduced in males and correlated with higher numbers of intrahepatic regulatory T cells (Tregs). Similar effects were observed in woodchuck hepatitis virus transgenic mice immunized with a DNA prime-recombinant adenovirus boost vaccination protocol. Male mice showed functionally suppressed woodchuck hepatitis virus–specific CD8+ T-cell responses in the liver and significantly higher numbers of intrahepatic Tregs compared to females. Blockade of Treg responses in male mice led to augmented effector functions of specific CD8+ T cells and subsequently improved virus control in both models of transient and persistent hepadnaviral infection. Conclusion: The functionality of virus-specific CD8+ T cells in male mice was suppressed by intrahepatic Tregs and inversely correlated with levels of hepadnaviral DNA and viral protein; the induction of intrahepatic Tregs by viral replication and/or protein levels may explain the gender-related differences in the outcomes of HBV infection and limit the success of immunotherapeutic strategies in male patients. (Hepatology 2017;66:69–83).

StephenW

男性低乙型肝炎病毒特异性T细胞反应与鼠模型中的高调节性T细胞数量相关
作者

首次发布：2017年5月26日全面引发历史
DOI：10.1002 / hep.29155查看/保存引用
引用（CrossRef）：0篇文章检查更新

资金信息

潜在的利益冲突：没有报告。

由德意志民主共和国（TRR60和RTG1949）支持。

AD Kosinska和M. Roggendorf目前的地址是：德国慕尼黑技术大学/亥姆霍兹中心病毒学研究所。 L. Pishraft-Sabet现在的地址是：伊朗Karaj的农业研究，教育和推广组织（AREEO）的拉齐疫苗和血清研究所。

抽象

乙型肝炎病毒（HBV）感染在疾病进展，疾病进展和肝细胞癌发展中发现显着的性别相关差异。 HBV复制和病毒蛋白水平的性别相关差异可能与宿主中不同的HBV特异性免疫反应相关。在本研究中，我们研究了两种不同小鼠模型中性别对HBV特异性免疫应答的影响，持续性肝炎病毒感染;流行动力注射与HBV基因组模拟了急性HBV感染，研究了治疗性接种的疗效。与女性小鼠相比，男性HBV DNA和蛋白水平总数检测到总数。尽管HBV动态注射与HBV基因组相似，但肝内HBV特异性分化组8 - 阳性（CD8 +）T细胞数量相似，但与男性相比有显着降低，与肝内调节T细胞数目有关（Tregs） 。用DNA重组腺病毒加强免疫接种方案免疫的土拨鼠肝炎病毒转基因小鼠的类似作用。雄性小鼠显示功能性抑制土拨鼠肝炎病毒 - 特异性CD8 + T细胞在肝脏中的反应和明显较多的肝内Tregs与女性相比。在雄性小鼠中阻断Treg反应导致特异性CD8 + T细胞的增强的效应子功能，并随后改进了两种模型的瞬时和持续肝炎病毒感染的病毒控制。男性小鼠中病毒特异性CD8 + T细胞的功能受到肝内Treg的抑制，与肝炎病毒DNA和病毒蛋白水平相反;通过病毒复制和/或蛋白质水平诱导肝内Tregs可以解释HBV感染结局的性别相关差异，并限制男性患者免疫治疗策略的成功。 （Hepatology 2017; 66：69-83）。