I型干扰素信号通过减少抗原表达来预防乙型肝炎病毒特异性T

StephenW

Type I Interferon Signaling Prevents Hepatitis B Virus-Specific T Cell Responses by Reducing Antigen Expression
Keigo Kawashima, Masanori Isogawa, Susumu Hamada-Tsutsumi, Ian Baudi, Satoru Saito, Atsushi Nakajima, Yasuhito Tanaka
J.-H. James Ou, Editor
DOI: 10.1128/JVI.01099-18

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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_IND [Aa], C_JPN22 [C22], and D_IND60 [D60]) that express various amounts of HBV antigens into the livers of C57BL/6 (B6) (H-2b) mice and B10.D2 (H-2d) mice. 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 H-2d mice. 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–/–) (H-2b) mice. 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 small interfering RNA (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 contributions 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 rates between HBV clones after hydrodynamic transduction were 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 the HBV-specific CD8+ T cell response is regulated primarily by the initial antigen expression level.

    Copyright © 2018 American Society for Microbiology.

StephenW

I型干扰素信号通过减少抗原表达来预防乙型肝炎病毒特异性T细胞应答
Keigo Kawashima，Masanori Isogawa，Susumu Hamada-Tsutsumi，Ian Baudi，Satoru Saito，Atsushi Nakajima，Yasuhito Tanaka
J.-H. James Ou，编辑
DOI：10.1128 / JVI.01099-18

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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_IND [Aa]，C_JPN22 [C22]和D_IND60 [D60]），将不同量的HBV抗原表达到肝脏中C57BL / 6（B6）（H-2b）小鼠和B10.D2（H-2d）小鼠。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。在H-2d小鼠中，HBV克隆之间的这些差异大大减少。有趣的是，B6小鼠中HBV特异性CD8 + T细胞应答的大小与HBV转导早期的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 - / - ）（H-2b）小鼠中诱导了对克隆C22的稳健的HBV特异性CD8 + T细胞应答。 IFN-αβR - / - 小鼠中HBV特异性CD8 + T细胞对C22反应的诱导反映了HBV抗原表达增强，因为HBV特异性小干扰RNA（siRNA）抑制抗原表达减弱了IFN中HBV特异性T细胞反应-αβR - / - 小鼠和HBV表达延长。总之，这些结果表明HBV遗传变异和I型干扰素信号传导通过调节初始抗原表达水平来确定HBV特异性CD8 + T细胞应答的量级。

重要性乙型肝炎病毒（HBV）引起急性和慢性感染，全世界约有2.4亿人慢性感染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。

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