Department of Gastroenterology and Hepatology, Yokohama City University School of Medicine, Yokohama, Japan.
Department of Virology and Liver Unit, Nagoya City University Graduate School of Medical Sciences, Nagoya, Japan.
J Virol. 2018 Nov 12;92(23). doi: 10.1128/JVI.01099-18. Print 2018 Dec 1.
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. 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.
为了清除乙型肝炎病毒 (HBV)，需要产生强大的病毒特异性 CD8 T 细胞反应。然而，决定 HBV 特异性 CD8 T 细胞反应大小的因素还了解甚少。为了研究 HBV 遗传变异对 HBV 特异性 CD8 T 细胞反应的影响，我们将三种表达不同 HBV 抗原量的 HBV 克隆（Aa_IND [Aa]、C_JPN22 [C22]和 D_IND60 [D60]）引入 C57BL/6（B6）（H-2b）小鼠和 B10.D2（H-2d）小鼠的肝脏中。在 B6 小鼠中，C22 克隆几乎不能诱导 HBV 特异性 CD8 T 细胞反应，而且持续时间最长，而 D60 克隆则能诱导强烈的 HBV 特异性 CD8 T 细胞反应，并迅速被清除。这些 HBV 克隆之间的差异在 H-2d 小鼠中大大减少。有趣的是，B6 小鼠中 HBV 特异性 CD8 T 细胞反应的大小与 HBV 转导早期 HB 核心抗原的表达水平有关。令人惊讶的是，在干扰素-α/β受体缺陷（IFN-αβR）（H-2b）小鼠中，能够诱导对 C22 克隆的强烈 HBV 特异性 CD8 T 细胞反应。IFN-αβR 小鼠中 C22 克隆诱导的 HBV 特异性 CD8 T 细胞反应反映了 HBV 抗原表达的增强，因为 HBV 特异性小干扰 RNA（siRNA）抑制抗原表达会减弱 IFN-αβR 小鼠中的 HBV 特异性 T 细胞反应并延长 HBV 的表达。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决定 HBV 特异性 CD8 T 细胞反应的大小。乙型肝炎病毒 (HBV) 可引起急性和慢性感染，全世界约有 2.4 亿人慢性感染 HBV。人们普遍认为，病毒特异性 CD8 T 细胞反应是清除 HBV 所必需的。然而，HBV 特异性 CD8 T 细胞反应的诱导与遗传变异和先天免疫反应的相对贡献尚不完全清楚。在这项研究中，我们发现，水力转导后不同 HBV 克隆的清除率与 HBV 特异性 CD8 T 细胞反应的大小和初始 HB 核心抗原的表达有关。令人惊讶的是，I 型干扰素信号通过减少早期 HBV 抗原表达来负调控 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。
