在肝脏免疫效果：是CD8 + T细胞的命运由环境决定？

StephenW

Review
Immune outcomes in the liver: Is CD8 T cell fate determined by the environment?

    Yik Chun Wong1, , , Szun Szun Tay1, ‡, Geoffrey W. McCaughan2, David G. Bowen1, †, Patrick Bertolino1, †, ,

    1 Liver Immunology Group, Centenary Institute and AW Morrow Gastroenterology and Liver Centre, University of Sydney and Royal Prince Alfred Hospital, Sydney, NSW, Australia
    2 Liver Cancer and Injury Group, Centenary Institute and AW Morrow Gastroenterology and Liver Centre, University of Sydney and Royal Prince Alfred Hospital, Sydney, NSW, Australia

    Received 30 March 2015, Revised 22 May 2015, Accepted 26 May 2015, Available online 20 June 2015

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        doi:10.1016/j.jhep.2015.05.033
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Summary

The liver is known for its tolerogenic properties. This unique characteristic is associated with persistent infection of the liver by the hepatitis B and C viruses. Improper activation of cellular adaptive immune responses within the liver and immune exhaustion over time both contribute to ineffective cytotoxic T cell responses to liver-expressed antigens in animal models, and likely play a role in incomplete clearance of chronic hepatitis virus infections in humans. However, under some conditions, functional immune responses can be elicited against hepatic antigens, resulting in control of hepatotropic infections. In order to develop improved therapeutics in immune-mediated chronic liver diseases, including viral hepatitis, it is essential to understand how intrahepatic immunity is regulated. This review focuses on CD8 T cell immunity directed towards foreign antigens expressed in the liver, and explores how the liver environment dictates the outcome of intrahepatic CD8 T cell responses. Potential strategies to rescue unresponsive CD8 T cells in the liver are also discussed.
Abbreviations

    APCs, antigen-presenting cells; CTLs, cytotoxic CD8 T cells; DCs, dendritic cells; HBV, hepatitis B virus; HCV, hepatitis C virus; ICAM-1, intercellular adhesion molecule-1; IL, interleukin; LCMV, lymphocytic choriomeningitis virus; LNs, lymph nodes; LSECs, liver sinusoidal endothelial cells; MHC-I, major histocompatibility complex class I; PD-1, programmed death 1; PD-L1, programmed death ligand-1; PD-L2, programmed death ligand-2; rAAV, recombinant adeno-associated virus; TCR, T cell receptor; TLR, toll-like receptor

Keywords

    Cytotoxic T cells; Tolerance; Immunity; Viral hepatitis; Antigen load; CD8 T cell exhaustion; CD4 T cell help

Introduction

The liver is the target organ of the hepatitis B and C viruses (HBV, HCV), which are associated with the development of chronic liver disease. It is estimated that over 500 million people worldwide are persistently infected with HBV or HCV, representing a major global health problem of considerable human and financial costs. However, HBV and HCV infections are not always persistent: more than 90% of HBV infection in adults and 20% of HCV infections result in viral control or clearance. The reasons why the same viruses persist in some individuals but are cleared in others, and why other hepatotropic viruses, such as hepatitis A, are more effectively eliminated remain unclear. It is likely that these two divergent outcomes are related to the paradoxical immunological properties of the liver itself.

Although effective immune response can be elicited within the liver, under some circumstances the liver induces a state of immune unresponsiveness known as tolerance. This phenomenon underpins the spontaneous acceptance of allogeneic liver transplants observed in several animal models (reviewed in [1]). Injection of antigens via the portal route resulting in direct delivery to the liver [2], and targeting gene expression to the liver [3], both often lead to tolerance. While this intriguing tolerogenic property of the liver has long been known, the mechanisms underlying this phenomenon are not yet completely understood. It is tempting to speculate that some pathogens exploit this tolerogenic property to persist within the liver.

The hallmark of an efficient immune response is the generation of effector cells that eliminate infected cells and/or secrete cytokines that suppress pathogen replication or recruit other arms of the immune response to promote pathogen clearance. CD8 T cells are critical for pathogen clearance, as after activation, they acquire the ability to kill infected cells and secrete cytokines which have direct anti-microbial properties (reviewed in [4]). In the liver, functional cytotoxic CD8 T cells (CTLs) are essential for the resolution of acute HBV [5] and HCV [6] infections. Consistent with this, virus-specific CD8 T cells isolated from patients chronically infected with HBV or HCV have impaired function. This failure to generate a productive anti-viral response results in persistent viral replication that promotes chronic liver disease [7], [8], [9] and [10]. Therefore, the induction of a functional CD8 T cell response against hepatic antigens is associated with better clinical outcomes. In this review, we first discuss the mechanism of T cell activation and the signals required for generating an optimal CD8 T cell response, then the factors that might lead to loss of CD8 T cell responses to liver-expressed antigen and thus promote chronic hepatotropic infections.

StephenW

回顾
在肝脏免疫效果：是CD8 + T细胞的命运由环境决定？

    奕淳Wong1，，Szun Szun Tay1，‡，杰弗里·W·McCaughan2，戴维·Bowen1，†，帕特里克Bertolino1，†，

    1肝脏免疫学组，百周年纪念研究所和AW莫罗胃肠病学和肝脏中心，悉尼大学和皇家阿尔弗雷德王子医院，悉尼，新南威尔士，澳大利亚
    2肝癌和损伤组，百周年纪念研究所和AW莫罗胃肠病学和肝脏中心，悉尼皇家阿尔弗雷德王子医院，悉尼大学，澳大利亚

    收到30 2015年三月，修订22 2015年5月，接受26 2015年5月，可在线20 2015年6月

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        DOI：10.1016 / j.jhep.2015.05.033
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摘要

肝脏是著名的免疫耐受性。这种独特的特性与肝脏由乙型和丙型肝炎病毒的持续性感染相关联。不当活化的肝和免疫耗竭随时间都在动物模型中造成无效的细胞毒性T细胞对肝脏表达的抗原的细胞内适应性免疫反应，并有可能在慢性肝炎病毒感染在人中不完整的间隙发挥作用。然而，在某些条件下，功能的免疫应答可引起抗肝脏抗原，导致嗜肝感染的控制。为了发展在免疫介导的慢性肝脏疾病，包括病毒性肝炎改进的治疗剂，有必要了解如何肝内免疫调节。这次审查的重点CD8 + T细胞免疫针对在肝中表达外来抗原，并探讨如何肝脏环境使然肝内CD8 + T细胞反应的结果。潜在的战略，以拯救反应迟钝CD8 T细胞在肝脏中进行了讨论。
缩写

    的APC的抗原呈递细胞;的CTL，细胞毒性CD8 + T细胞;的DC，树突细胞;乙肝病毒，B型肝炎病毒;丙型肝炎病毒，丙型肝炎病毒; ICAM-1，细胞间黏附分子-1;白细胞介素，白介素; LCMV，淋巴细胞性脉络丛脑膜炎病毒;淋巴结，淋巴结肿大; LSECs，肝窦内皮细胞; MHC-I，主要组织相容性复合物I类; PD-1，程序性死亡1; PD-L1的，程序性死亡配体1; PD-L2，程序性死亡配体2;腺相关病毒，重组腺相关病毒; TCR，T细胞受体; TLR，toll​​样受体

关键词

    细胞毒性T细胞;宽容;免疫;病毒性肝炎;抗原负载; CD8 T细胞的耗竭; CD4 + T细胞的帮助

简介

肝脏是乙型肝炎和丙型肝炎病毒（HBV，HCV），这是慢性肝病的发展相关联的靶器官。据估计，超过500万人在全球的持续感染乙肝或丙肝，占相当大的人力和财务成本的主要全球性健康问题。然而，HBV和HCV感染并不总是持续：在成人中的90％以上HBV感染和HCV感染的20％导致病毒控制或间隙。为什么同样的病毒坚持在一些个人，但都被清零别人，为什么其他嗜肝病毒，例如甲型肝炎，可以更有效地消除的原因仍不清楚。它很可能是这两个不同的结果都与肝脏本身的似是而非的免疫学特性。

虽然有效的免疫应答可以在肝脏内被引出，在某些情况下的肝诱导免疫反应迟钝称为耐受状态。这种现象支撑在几个动物模型中观察到同种异体肝脏移植的自发接受（在[1]中综述）。注射经门路线抗原导致直接递送至肝[2]，和基因表达靶向至肝脏的[3]，二者常常导致耐受性。而肝脏这一有趣致耐受性属性早已公知，底层这种现象的机制尚未完全了解。我们很容易推测，某些病原体利用这种耐受性肝脏内持续存在。

的有效免疫反应的标志是效应细胞，从而消除感染细胞和/或分泌的细胞因子抑制病原体的复制或招募的免疫应答的其他武器，以促进病原体清除的产生。 CD8 T细胞是病原体清除关键的，因为在激活后，他们获得杀死被感染的细胞和分泌细胞因子具有直接的抗微生物性质的能力（综述[4]）。在肝脏中，功能性细胞毒性CD8 + T细胞（CTL）是用于急性HBV [5]和HCV [6]感染的分辨率是必不可少的。与此相一致，病毒特异性CD8 T细胞从慢性感染HBV或HCV患者中分离具有受损的功能。这种故障，以产生一个高效的抗病毒反应的结果在持久的病毒复制，促进慢性肝病[7]，[8]，[9]和[10]。因此，抗肝脏抗原的功能性CD8 + T细胞应答的诱导与更好的临床结果相关联。在这次审查中，我们首先讨论了T细胞的活化需要产生一个最佳的CD8 + T细胞反应，那么因素可能导致的对CD8 T细胞应答损失肝表达的抗原，从而促进慢性嗜肝感染的机制和信号。

StephenW

这是一个很有教育意义回顾.
它有助于我们理解免疫耐受，为什么降低血清病毒抗原可以帮助全面恢复免疫功能.
全文: http://www.sciencedirect.com/sci ... i/S0168827815004043