Lapierre Pascal, Janelle Valérie, Langlois Marie-Pierre, Tarrab Esther, Charpentier Tania, Lamarre Alain
Immunovirology laboratory, Institut national de la recherche scientifique, INRS-Institut Armand-Frappier, Laval, Quebec, Canada.
Cell Mol Gastroenterol Hepatol. 2015 Feb 24;1(3):325-341.e1. doi: 10.1016/j.jcmgh.2015.02.002. eCollection 2015 May.
BACKGROUND & AIMS: The constant exposure of the liver to food and bacterial antigens through the mesenteric circulation requires it to maintain tolerance while preserving the ability to mount an effective immune response against pathogens. We investigated the contribution of the liver's tolerogenic nature on the establishment of chronic viral infections.
TTR-NP mice, which express the nucleoprotein (NP) of lymphocytic choriomeningitis virus (LCMV) specifically in hepatocytes under control of a modified transthyretin (TTR) promoter, were infected with the Armstrong (Arm) or WE acute strains of LCMV.
The infection persisted for at least 147 days in TTR-NP mice. Expression of NP by the liver induced a strong peripheral tolerance against NP that was mediated by interleukin-10-secreting CD4 regulatory T cells, leading to high PD-1 (programmed death-1) expression and reduced effector function of virus-specific T cells. Despite an active immune response against LCMV, peripheral tolerance against a single viral protein was sufficient to induce T-cell exhaustion and chronic LCMV Armstrong (Arm) or WE infection by limiting the antiviral T-cell response in an otherwise immunocompetent host. Regulatory T-cell depletion of chronically infected TTR-NP mice led to functional restoration of LCMV-specific CD4 and CD8 T cell responses and viral clearance.
Expression of a viral antigen by hepatocytes can induce a state of peripheral tolerance mediated by regulatory T cells that can lead to the establishment of a chronic viral infection. Strategies targeting regulatory T cells in patients chronically infected with hepatotropic viruses could represent a promising approach to restore functional antiviral immunity and clear infection.
肝脏通过肠系膜循环持续接触食物和细菌抗原，这要求它在维持对病原体产生有效免疫反应能力的同时保持耐受性。我们研究了肝脏的致耐受性特性对慢性病毒感染建立的影响。
在改良甲状腺转运蛋白（TTR）启动子控制下，TTR-NP小鼠在肝细胞中特异性表达淋巴细胞性脉络丛脑膜炎病毒（LCMV）的核蛋白（NP），用LCMV的阿姆斯特朗（Arm）株或WE急性株感染这些小鼠。
TTR-NP小鼠中的感染持续了至少147天。肝脏中NP的表达诱导了对NP的强烈外周耐受性，这由分泌白细胞介素-10的CD4调节性T细胞介导，导致病毒特异性T细胞的程序性死亡-1（PD-1）高表达和效应功能降低。尽管对LCMV有活跃的免疫反应，但对单一病毒蛋白的外周耐受性足以通过限制原本免疫功能正常宿主中的抗病毒T细胞反应来诱导T细胞耗竭和慢性LCMV阿姆斯特朗（Arm）株或WE株感染。慢性感染的TTR-NP小鼠的调节性T细胞耗竭导致LCMV特异性CD4和CD8 T细胞反应的功能恢复以及病毒清除。
肝细胞中病毒抗原的表达可诱导由调节性T细胞介导的外周耐受状态，这可能导致慢性病毒感染的建立。针对嗜肝病毒慢性感染患者的调节性T细胞的策略可能是恢复功能性抗病毒免疫力和清除感染的一种有前景的方法。
