Type I Interferon Signaling Prevents Hepatitis B Virus-Specific T Cell Responses by Reducing Antigen Expression
Type I Interferon Signaling Prevents Hepatitis B Virus-Specific T Cell Responses by Reducing Antigen Expression
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DOI：
10.1128/jvi.01099-18
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发表时间：
2018-12-01
影响因子：
5.4
通讯作者：
Tanaka, Yasuhito
中科院分区：
文献类型：
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作者：
Kawashima, Keigo;Isogawa, Masanori;Tanaka, Yasuhito
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，决定hbv特异性CD8(+) T细胞反应大小的因素尚不清楚。为了研究HBV遗传变异对HBV特异性CD8 T细胞应答的影响，我们将三个HBV克隆（Aa_IND [Aa]， C_JPN22 [C22]和D_IND60 [D60]）引入C57BL/6 (B6) （H-2b）小鼠和B10的肝脏中表达不同数量的HBV抗原。D2 （H-2d）小鼠。在B6小鼠中，克隆C22几乎没有引起hbv特异性CD8(+) T细胞反应，持续时间最长，而克隆D60引起hbv特异性CD8(+) T细胞反应强烈，并迅速被清除。在H-2d小鼠中，HBV克隆之间的这些差异大大减少。有趣的是，在HBV转导的早期阶段，B6小鼠中HBV特异性CD8(+) T细胞反应的大小与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（ifn - α - β R-/-） （H-2b）小鼠中诱导了hbv特异性CD8(+) T细胞对克隆C22的强烈反应。在ifn - α β R-/-小鼠中诱导HBV特异性CD8(+) T细胞对C22的反应反映了HBV抗原表达的增强，因为HBV特异性小干扰RNA （siRNA）抑制抗原表达减弱了ifn - α β R-/-小鼠中HBV特异性T细胞的反应并延长了HBV表达。总之，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决定HBV特异性CD8(+) T细胞应答的大小。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。一般认为，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在诱导hbv特异性CD8(+) T细胞应答中的相对作用尚不完全清楚。在这项研究中，我们发现HBV水动力转导后不同克隆之间的清除率与HBV特异性CD8(+) T细胞应答的大小和初始HB核心抗原表达有关。令人惊讶的是，I型干扰素信号通过降低早期HBV抗原表达负性调节HBV特异性CD8(+) T细胞反应。这些结果表明，hbv特异性CD8(+) T细胞反应的大小主要受初始抗原表达水平的调节。
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-alpha beta receptor-deficient (IFN-alpha beta R-/-) (H-2b) mice. The induction of HBV-specific CD8(+) T cell responses to C22 in IFN-alpha beta R-/- 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-alpha beta R-/- 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.