I型干扰素信号传导通过降低抗原表达来预防乙型肝炎病毒特

StephenW

J Virol. 2018 Sep 12. pii: JVI.01099-18. doi: 10.1128/JVI.01099-18. [Epub ahead of print]
Type I interferon signaling prevents hepatitis B virus-specific T cell responses by reducing antigen expression.
Kawashima K1,2, Isogawa M3, Hamada-Tsutsumi S2, Baudi I2, Saito S1, Nakajima A1, Tanaka Y3.
Author information

1
    Department of Gastroenterology and Hepatology, Yokohama City University School of Medicine, Yokohama, Japan.
2
    Department of Virology and Liver Unit, Nagoya City University Graduate School of Medical Sciences, Nagoya, Japan.
3
    Department of Virology and Liver Unit, Nagoya City University Graduate School of Medical Sciences, Nagoya, Japan [email protected] [email protected].

Abstract

Robust virus-specific CD8+ T cell responses are required for the clearance of hepatitis B virus (HBV). However, the factors that determine the magnitude of HBV-specific CD8+ T cell responses are poorly understood. To examine the impact of genetic variations of HBV on HBV-specific CD8+ T cell responses, we introduced three HBV clones (Aa, C22, D60) that express varying amounts of HBV antigens into the livers of C57BL/6 (B6) mice (H-2b) and B10.D2 mice (H-2d). In B6 mice, clone C22 barely induced HBV-specific CD8+ T cell responses and persisted the longest, while clone D60 elicited strong HBV-specific CD8+ T cell responses and was rapidly cleared. These differences between HBV clones largely diminished in B10.D2 mice (H-2d). Interestingly, the magnitude of HBV-specific CD8+ T cell responses in B6 mice was associated with the HB core antigen expression level during the early phase of HBV transduction. Surprisingly, robust HBV-specific CD8+ T cell responses to clone C22 were induced in interferon-α/β receptor-deficient (IFN-αβR-/-) mice (H-2b). The induction of HBV-specific CD8+ T cell responses to C22 in IFN-αβR-/- mice reflects enhanced HBV antigen expression because the suppression of antigen expression by HBV-specific siRNA attenuated HBV-specific T cell responses in IFN-αβR-/- mice and prolonged HBV expression. Collectively, these results suggest that HBV genetic variation and type I interferon signaling determine the magnitude of HBV-specific CD8+ T cell responses by regulating the initial antigen expression levels.IMPORTANCE Hepatitis B virus (HBV) causes acute and chronic infection, and approximately 240 million people are chronically infected with HBV worldwide. It is generally believed that virus-specific CD8+ T cell responses are required for the clearance of HBV. However, the relative contribution of genetic variation and innate immune responses to the induction of HBV-specific CD8+ T cell responses are not fully understood. In this study, we discovered that different clearance rate between HBV clones after hydrodynamic transduction was associated with the magnitude of HBV-specific CD8+ T cell responses and initial HB core antigen expression. Surprisingly, type I interferon signaling negatively regulated HBV-specific CD8+ T cell responses by reducing early HBV antigen expression. These results show that the magnitude of HBV-specific CD8+ T cell response is primarily regulated by the initial antigen expression level.

PMID:
    30209178
DOI:
    10.1128/JVI.01099-18

StephenW

J Virol。 2018年9月12日.pii：JVI.01099-18。 doi：10.1128 / JVI.01099-18。 [提前打印]
I型干扰素信号传导通过降低抗原表达来预防乙型肝炎病毒特异性T细胞应答。
Kawashima K1,2，Isogawa M3，Hamada-Tsutsumi S2，Baudi I2，Saito S1，Nakajima A1，Tanaka Y3。
作者信息

1
    日本横滨市横滨市立大学医学院消化内科和肝病学系。
2
    日本名古屋市名古屋市立大学医学研究科病毒学与肝科。
3
    日本名古屋市名古屋市立大学医学研究科病毒学与肝科，misogawa @med.nagoya-cu.ac.jp [email protected]。

抽象

清除乙型肝炎病毒（HBV）需要强大的病毒特异性CD8 + T细胞应答。然而，很难理解决定HBV特异性CD8 + T细胞反应程度的因素。为了检查HBV遗传变异对HBV特异性CD8 + T细胞反应的影响，我们引入了三种HBV克隆（Aa，C22，D60），它们将不同量的HBV抗原表达到C57BL / 6（B6）小鼠的肝脏中（H -2b）和B10.D2小鼠（H-2d）。在B6小鼠中，克隆C22几乎不诱导HBV特异性CD8 + T细胞应答并持续时间最长，而克隆D60引起强烈的HBV特异性CD8 + T细胞应答并迅速清除。 HBV克隆之间的这些差异在B10.D2小鼠（H-2d）中大大减少。有趣的是，在HBV转导的早期阶段，B6小鼠中HBV特异性CD8 + T细胞应答的大小与HB核心抗原表达水平相关。令人惊讶的是，在干扰素-α/β受体缺陷型（IFN-αβR - / - ）小鼠（H-2b）中诱导了对克隆C22的稳健的HBV特异性CD8 + T细胞应答。在IFN-αβR - / - 小鼠中诱导HBV特异性CD8 + T细胞对C22的反应反映了HBV抗原表达增强，因为HBV特异性siRNA抑制抗原表达减弱了IFN-αβR中HBV特异性T细胞反应 - / - 小鼠和HBV表达延长。总的来说，这些结果表明HBV遗传变异和I型干扰素信号通过调节初始抗原表达水平来确定HBV特异性CD8 + T细胞应答的程度。重要性乙型肝炎病毒（HBV）引起急性和慢性感染，约2.4亿人们在世界范围内长期感染HBV。通常认为，清除HBV需要病毒特异性CD8 + T细胞应答。然而，遗传变异和先天免疫应答对HBV特异性CD8 + T细胞应答诱导的相对贡献尚不完全清楚。在本研究中，我们发现水动力学转导后HBV克隆之间的不同清除率与HBV特异性CD8 + T细胞应答和初始HB核心抗原表达的程度相关。令人惊讶的是，I型干扰素信号通过降低早期HBV抗原表达来负调节HBV特异性CD8 + T细胞应答。这些结果表明，HBV特异性CD8 + T细胞应答的大小主要受初始抗原表达水平的调节。

结论：
    30209178
DOI：
    10.1128 / JVI.01099-18

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