Chronic hepatitis B virus (HBV) infection has been characterized by lack of effective adaptive immune responses which are vital for the viral clearance. However, very little is known about the dynamics of adaptive immune responses during the early phase of chronic HBV infection especially in spleen and liver. Here, we used the hydrodynamic injection (HDI) mouse model to kinetically characterize differences in the features of adaptive immunity, including the frequencies, phenotypes and function of antigen-presenting cells and T cells in the spleen, peripheral blood mononuclear cells (PBMCs) and liver, of chronic versus acute-resolving HBV replication (AR). We found that mice with AR mice and mice with chronic HBV replication (CH) mice showed early splenomegaly accompanied by T cell expansion in spleen but not in liver after HDI. Interestingly, the early and continuous increase in HBV-specific CD8+ T cells in spleen of CH mice was comparable to that in the AR mice. However, the splenic T cells of CH mice showed no activation phenotype compared with those in AR mice. Besides, increases in activated effector CD8+ T cells in PBMCs and liver at later time points were only observed in AR mice but not CH mice. CH mice also showed insufficient expansion of dendritic cells (DCs) in spleen and increased programmed death-1 expression in DCs of the liver compared to AR mice. The adoptive transfer of total splenocytes or splenic CD8+ T cells of AR mice to CH mice demonstrated that their ability to break HBV tolerance varies at different stages of HBV clearance. Moreover, the adoptive transfer of splenocytes from AR mice induce functional activation of endogenous HBV-specific CD8+ T cells of CH mice. Our results suggest that early T cell priming and expansion initially happens in the periphery after HBV antigen exposure in acute-resolving and chronic replication. The paucity of T cell activation, and subsequent migration and liver infiltration is a key feature of the adaptive immune responses during the early phase of CH, which is probably caused by the dysfunction of DCs.

中文翻译：

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一项系统比较揭示了急性消退和慢性 HBV 复制的早期适应性免疫反应的动态差异

慢性乙型肝炎病毒 (HBV) 感染的特点是缺乏对病毒清除至关重要的有效适应性免疫反应。然而，人们对慢性 HBV 感染早期尤其是脾脏和肝脏中的适应性免疫反应动力学知之甚少。在这里，我们使用流体动力注射 (HDI) 小鼠模型来动力学表征适应性免疫特征的差异，包括脾脏、外周血单核细胞 (PBMC) 和肝脏，慢性与急性 HBV 复制 (AR)。我们发现，携带 AR 小鼠和携带慢性 HBV 复制 (CH) 小鼠的小鼠在 HDI 后表现出早期脾肿大并伴有脾脏而非肝脏中的 T 细胞扩增。有趣的是，CH 小鼠脾脏中 HBV 特异性 CD8+ T 细胞的早期持续增加与 AR 小鼠相当。然而，与 AR 小鼠相比，CH 小鼠的脾脏 T 细胞没有显示出激活表型。此外，仅在 AR 小鼠而非 CH 小鼠中观察到 PBMC 和肝脏中活化效应 CD8+ T 细胞在后期时间点的增加。与 AR 小鼠相比，CH 小鼠脾脏中树突状细胞 (DC) 的扩张不足，肝脏 DC 中程序性死亡-1 表达增加。将 AR 小鼠的总脾细胞或脾脏 CD8+ T 细胞过继转移至 CH 小鼠表明，它们打破 HBV 耐受的能力在 HBV 清除的不同阶段有所不同。此外，AR 小鼠脾细胞的过继转移诱导 CH 小鼠内源性 HBV 特异性 CD8+ T 细胞的功能激活。我们的结果表明，早期 T 细胞启动和扩增最初发生在 HBV 抗原暴露后的外周急性分解和慢性复制中。T 细胞活化的缺乏以及随后的迁移和肝脏浸润是 CH 早期适应性免疫反应的一个关键特征，这可能是由 DC 功能障碍引起的。