肝病毒抗原的表达通过生成调节性T细胞导致慢性感染

StephenW

Cell Mol Gastroenterol Hepatol. 2015 Feb 24;1(3):325-341.e1. doi: 10.1016/j.jcmgh.2015.02.002. eCollection 2015.
Expression of Viral Antigen by the Liver Leads to Chronic Infection Through the Generation of Regulatory T Cells.Lapierre P1, Janelle V1, Langlois MP1, Tarrab E1, Charpentier T1, Lamarre A1.
Author information

• 1Immunovirology laboratory, Institut national de la recherche scientifique, INRS-Institut Armand-Frappier, Laval, Quebec, Canada.
  

AbstractBACKGROUND & 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.
METHODS: 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.
RESULTS: 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.
CONCLUSIONS: 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.

StephenW

Cell Mol Gastroenterol Hepatol。 2015 Feb 24; 1（3）：325-341.e1。 doi：10.1016 / j.jcmgh.2015.02.002。 eCollection 2015。
肝病毒抗原的表达通过生成调节性T细胞导致慢性感染。
Lapierre P1，Janelle V1，Langlois MP1，Tarrab E1，Charpentier T1，Lamarre A1。
作者信息

    1Immunovirology laboratory，Institut national de la recherche scientifique，INRS-Institut Armand-Frappier，Laval，Quebec，Canada。

抽象
背景与目的：

肝脏通过肠系膜循环持续暴露于食物和细菌抗原需要其保持耐受性，同时保持对病原体产生有效的免疫应答的能力。我们调查了肝脏致耐受性对慢性病毒感染建立的贡献。
方法：

用Armstrong（Arm）或WE急性株LCMV感染在表达改良甲状腺素运载蛋白（TTR）启动子控制下的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）的TTR-NP小鼠。
结果：

感染在TTR-NP小鼠中持续至少147天。 NP的表达由肝诱导由介导白细胞介素-10分泌性CD4 +调节性T细胞介导的NP的强外周耐受，导致高PD-1（程序性死亡-1）表达和降低的病毒特异性T细胞的效应子功能。尽管针对LCMV具有主动免疫应答，但对单一病毒蛋白的外周耐受性通过限制在其它免疫活性宿主中的抗病毒T细胞应答而足以诱导T细胞衰竭和慢性LCMV Armstrong（Arm）或WE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细胞应答和病毒清除的功能恢复。
结论：

病毒抗原通过肝细胞的表达可以诱导由调节性T细胞介导的外周耐受状态，其可以导致慢性病毒感染的建立。在慢性感染肝炎病毒的患者中靶向调节性T细胞的策略可以代表恢复功能性抗病毒免疫和清除感染的有希望的方法。