肝脏中抗病毒免疫的结果由感染肝细胞中表达的抗原水平决

StephenW

Hepatology. 2018 May 5. doi: 10.1002/hep.30080. [Epub ahead of print]
Outcome of anti-viral immunity in the liver is shaped by the level of antigen expressed in infected hepatocytes.
Manske K1, Kallin N1, König V1, Schneider A1, Kurz S1, Bosch M1, Welz M2, Cheng RL2, Bengsch B3, Steiger K4, Protzer U5,6, Thimme R3, Knolle PA1,2,6, Wohlleber D1.
Author information

1
    Institute of Molecular Immunology and Experimental Oncology, University Hospital Klinikum rechts der Isar, Technical University of Munich, Germany.
2
    Institute of Experimental Immunology, University Hospital Bonn, University of Bonn, Germany.
3
    University Hospital Freiburg, University of Freiburg, Germany.
4
    Institute of Pathology, Technical University of Munich, Germany.
5
    Institute of Virology University Hospital rechts der Isar, Technical University of Munich and Institute of Virology, Helmholtz Center for Environment and Health.
6
    German Center for Infection Research, Munich site.

Abstract

The liver bears unique immune-properties supporting both immune tolerance and immunity, but the mechanisms responsible for clearance versus persistence of virus-infected hepatocytes remains unclear. Here, we dissect the factors determining the outcome of anti-viral immunity using novel recombinant adenoviruses reflecting the hepatropism and -trophism of hepatitis viruses. We generated replication-deficient adenoviruses with equimolar ovalbumin, luciferase and GFP-expression driven by strong ubiquitous CMV-promoter (Ad-CMV-GOL) or by 100-fold weaker, yet hepatocyte-specific Transthyretin(TTR)-promoter (Ad-TTR-GOL). Using in vivo-bioluminescence to quantitatively and dynamically image luciferase activity, we demonstrate that Ad-TTR-GOL-infection always persisted whereas Ad-CMV-GOL-infection was always cleared, independent of numbers of infected hepatocytes. Failure to clear Ad-TTR-GOL-infection involved mechanisms acting during initiation as well as execution of antigen-specific immunity. First, hepatocyte-restricted antigen-expression led to delayed and curtailed T-cell-expansion - 10.000-fold after Ad-CMV-GOL versus 150-fold after Ad-TTR-GOL-infection. Second, CD8 T-cells primed towards antigens selectively expressed by hepatocytes showed high PD-1/Tim-3/LAG-3/CTLA-4/CD160 expression-levels similar to that seen in chronic hepatitis B. Third, Ad-TTR-GOL but not Ad-CMV-GOL-infected hepatocytes escaped killing by effector T-cells while still inducing high PD-1/Tim-3/LAG-3/CTLA-4/CD160 expression indicating different thresholds of TCR-signaling relevant for triggering effector functions compared to exhaustion.
CONCLUSION:

Our study identifies deficits in generation of CD8 T-cell immunity towards hepatocyte-expressed antigens and escape of infected hepatocytes expressing low viral antigen levels from effector T-cell-killing as independent factors promoting viral persistence. This highlights the importance to address both, restauration of CD8 T-cell dysfunction and overcoming local hurdles of effector T-cell function to eliminate virus-infected hepatocytes. This article is protected by copyright. All rights reserved.

© 2018 by the American Association for the Study of Liver Diseases.
KEYWORDS:

CD8 T-cells; dynamic of antiviral immunity; hepatitis

PMID:
    29729204
DOI:
    10.1002/hep.30080

StephenW

肝病。 2018年5月5日，doi：10.1002 / hep.30080。 [电子版提前打印]
肝脏中抗病毒免疫的结果由感染肝细胞中表达的抗原水平决定。
Manske K1，Kallin N1，KönigV1，Schneider A1，Kurz S1，Bosch M1，Welz M2，Cheng RL2，Bengsch B3，Steiger K4，Protzer U5,6，Thimme R3，Knolle PA1,2,6，Wohlleber D1。
作者信息

1
德国慕尼黑工业大学Klinikum rechts der Isar大学医院分子免疫与实验肿瘤研究所。
2
德国波恩大学波恩大学附属医院实验免疫学研究所。
3
弗赖堡大学医院，德国弗莱堡大学。
4
德国慕尼黑理工大学病理学研究所。
五
德国伊萨尔大学病毒学研究所，慕尼黑理工大学和赫尔姆霍茨环境与健康中心病毒学研究所。
6
德国慕尼黑感染研究中心网站。

抽象

肝具有支持免疫耐受和免疫力的独特免疫特性，但负责清除病毒的病毒与感染病毒的肝细胞的持续存在的空间仍不清楚。在这里，我们使用反映肝炎病毒的遗传学和遗传学的新型重组腺病毒，分析确定抗病毒免疫的结果的因素。我们利用强泛素CMV启动子（Ad-CMV-GOL）或100倍较弱但肝细胞特异性转甲状腺素蛋白（TTR）启动子（Ad-TTR）启动的等摩尔卵白蛋白，萤光素酶和GFP-表达产生复制缺陷型腺病毒-GOL）。使用体内生物发光来定量和动态地显示荧光素酶活性，我们证明Ad-TTR-GOL-感染总是持续存在，而Ad-CMV-GOL-感染总是被清除，不受感染的肝细胞数量的影响。未能清除Ad-TTR-GOL-感染涉及影响起始过程中的机制以及抗原特异性免疫的执行。首先，肝细胞限制性抗原表达导致延迟和减少的T细胞扩增 - 在Ad-CMV-GOL之后为10.000倍，而在Ad-TTR-GOL-感染之后为150倍。其次，CD8 T细胞开始接近。通过肝素选择性表达表明高水平的PD-1 / Tim-3 / LAG-3 / CTLA-4 / CD160表达水平类似于在慢性乙型肝炎中所见。第三，Ad-TTR-GOL而不是Ad-CMV-GOL感染的肝细胞逃逸效应T细胞的杀伤，同时仍然诱导高PD-1 / Tim-3 / LAG-3 / CTLA-4 / CD160表达，表明与耗竭相比，触发效应子功能相关的不同阈值的TCR-信号传导。
结论：

我们的研究发现CD8 T细胞对肝细胞表达抗原产生的免疫缺陷以及表达低病毒抗原水平的效应T细胞杀伤作为促进病毒持续存在的独立因子的感染肝细胞的逃逸。这突出显示了解决CD8 T细胞功能障碍的重建和克服效应T细胞功能的局部障碍以消除病毒感染的肝细胞的重要性。本文受版权保护。版权所有。

©美国肝病研究协会版权所有©2018年。
关键词：

CD8 T细胞;抗病毒免疫力的动态;

结论：
29729204
DOI：
10.1002 / hep.30080