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发表于 2019-1-17 08:12 |只看该作者 |倒序浏览 |打印
Nat Commun. 2019 Jan 15;10(1):221. doi: 10.1038/s41467-018-08096-8.
Breakdown of adaptive immunotolerance induces hepatocellular carcinoma in HBsAg-tg mice.
Zong L1,2, Peng H1,2, Sun C1,2, Li F1,2, Zheng M3, Chen Y1,2, Wei H1,2, Sun R1,2, Tian Z4,5.
Author information

1
    Division of Molecular Medicine, Hefei National Laboratory for Physical Sciences at Microscale, the CAS Key Laboratory of Innate Immunity and Chronic Disease, School of Life Sciences, University of Science and Technology of China, 230027, Hefei, Anhui, China.
2
    Institute of Immunology, University of Science and Technology of China, 230027, Hefei, Anhui, China.
3
    Clinical Laboratory, The First Affiliated Hospital of Anhui Medical University, 230022, Hefei, Anhui, China.
4
    Division of Molecular Medicine, Hefei National Laboratory for Physical Sciences at Microscale, the CAS Key Laboratory of Innate Immunity and Chronic Disease, School of Life Sciences, University of Science and Technology of China, 230027, Hefei, Anhui, China. [email protected].
5
    Institute of Immunology, University of Science and Technology of China, 230027, Hefei, Anhui, China. [email protected].

Abstract

Hepatitis B virus (HBV) can induce chronic inflammation, cirrhosis, and eventually hepatocellular carcinoma (HCC). Despite evidence suggesting a link between adaptive immunity and HBV-related diseases in humans, the immunopathogenic mechanisms involved are seldom described. Here we show that expression of TIGIT, a promising immune checkpoint in tumor immunotherapy, increases with age on hepatic CD8+ T cells in HBsAg-transgenic (HBs-tg) mice whose adaptive immune system is tolerant to HBsAg. TIGIT blockade or deficiency leads to chronic hepatitis and fibrosis, along with the emergence of functional HBsAg-specific cytotoxic T lymphocytes (CTLs), suggesting adaptive immune tolerance could be broken by TIGIT blockade or deficiency. Importantly, HBsAg vaccination further induces nonresolving inflammation and HCC in a CD8+ T cell-dependent manner in TIGIT-blocked or -deficient HBs-tg mice. Therefore, CD8+ T cells play an important role in adaptive immunity-mediated tumor progression and TIGIT is critical in maintenance of liver tolerance by keeping CTLs in homeostatic balance.

PMID:
    30644386
DOI:
    10.1038/s41467-018-08096-8

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发表于 2019-1-17 08:13 |只看该作者
Nat Commun。 2019年1月15日; 10(1):221。 doi:10.1038 / s41467-018-08096-8。
适应性免疫耐受的分解诱导HBsAg-tg小鼠的肝细胞癌。
Zong L1,2,Peng H1,2,Sun C1,2,Li F1,2,Zheng M3,Chen Y1,2,Wei H1,2,Sun R1,2,Tian Z4,5。
作者信息

1
    中国科学技术大学生命科学学院分子医学科,合肥微尺度物质科学国家实验室,中国科学院先天免疫与慢性病中科院重点实验室,安徽合肥230027
2
    中国科学技术大学免疫学研究所,安徽合肥230027
3
    安徽医科大学第一附属医院临床实验室,安徽合肥230022
4
    中国科学技术大学生命科学学院分子医学科,合肥微尺度物质科学国家实验室,中国科学院先天免疫与慢性病中科院重点实验室,安徽合肥230027 [email protected]

    中国科学技术大学免疫学研究所,安徽合肥230027 [email protected]

抽象

乙型肝炎病毒(HBV)可诱导慢性炎症,肝硬化,并最终诱导肝细胞癌(HCC)。尽管有证据表明适应性免疫与人类HBV相关疾病之间存在联系,但很少涉及所涉及的免疫病理机制。在这里,我们显示TIGIT,肿瘤免疫治疗中有希望的免疫检查点,在HBsAg转基因(HBs-tg)小鼠肝脏CD8 + T细胞的表达增加,其适应性免疫系统耐受HBsAg。 TIGIT阻断或缺乏导致慢性肝炎和纤维化,以及功能性HBsAg特异性细胞毒性T淋巴细胞(CTL)的出现,表明TIGIT阻断或缺乏可以打破适应性免疫耐受。重要的是,HBsAg疫苗接种在TIGIT阻断或缺陷的HBs-tg小鼠中进一步诱导CD8 + T细胞依赖性方式的非分辨性炎症和HCC。因此,CD8 + T细胞在适应性免疫介导的肿瘤进展中起重要作用,并且通过将CTL保持在稳态平衡中,TIGIT对维持肝耐受性至关重要。

结论:
    30644386
DOI:
    10.1038 / s41467-018-08096-8

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发表于 2019-1-17 08:18 |只看该作者

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发表于 2019-1-17 19:54 |只看该作者
Breakdown of adaptive immunotolerance induces hepatocellular carcinoma in HBsAg-tg mice
Lu Zong, Hui Peng, Cheng Sun, Fenglei Li, Meijuan Zheng, Yongyan Chen, Haiming Wei, Rui Sun & Zhigang Tian
Nature Communicationsvolume 10, Article number: 221 (2019) | Download Citation

Abstract
Hepatitis B virus (HBV) can induce chronic inflammation, cirrhosis, and eventually hepatocellular carcinoma (HCC). Despite evidence suggesting a link between adaptive immunity and HBV-related diseases in humans, the immunopathogenic mechanisms involved are seldom described. Here we show that expression of TIGIT, a promising immune checkpoint in tumor immunotherapy, increases with age on hepatic CD8+ T cells in HBsAg-transgenic (HBs-tg) mice whose adaptive immune system is tolerant to HBsAg. TIGIT blockade or deficiency leads to chronic hepatitis and fibrosis, along with the emergence of functional HBsAg-specific cytotoxic T lymphocytes (CTLs), suggesting adaptive immune tolerance could be broken by TIGIT blockade or deficiency. Importantly, HBsAg vaccination further induces nonresolving inflammation and HCC in a CD8+ T cell-dependent manner in TIGIT-blocked or -deficient HBs-tg mice. Therefore, CD8+ T cells play an important role in adaptive immunity-mediated tumor progression and TIGIT is critical in maintenance of liver tolerance by keeping CTLs in homeostatic balance.

Introduction
Chronic hepatitis B virus (HBV) infection affects more than 350 million people worldwide, despite the effective HBV vaccination among the young generation. Current antiviral treatment in the clinic is hardly effective to clear the virus1. Accumulating evidence has shown that chronic HBV (CHB) infection is an important risk factor for hepatocellular carcinoma (HCC)2,3,4. Virologists attribute HBV-mediated hepatocarcinogenesis to the integration of the viral DNA into the host DNA and oncoprotein regulatory X protein (HBx)5,6. However, it has been increasingly accepted that HBV is a non-cytopathic virus and HBV pathogenesis lies mostly in immune-mediated liver injury7,8,9,10, which triggers the development of HCC without viral transactivation, insertional mutagenesis, and genotoxic chemicals11. Despite such progress, the lack of appropriate animal models that mimic HBV-related HCC has impeded studies of immune mechanisms underlying HBV-induced HCC development.

The liver is a unique immune organ that favors the induction of immune tolerance rather than immune activation12. During CHB infection, virus-specific CD8+ T cells gradually acquire expression of numerous co-inhibitory receptors13,14,15,16, such as PD-1, CTLA-4, and Tim-317,18. Considering the contribution of immune-mediated injury in HBV pathogenesis, co-inhibitory receptors expressed by hepatic CD8+ T cells are important for preventing immune-driven pathology, but also result in CTL exhaustion and thereby limit viral clearance19,20. Blockade of co-inhibitory receptors, such as PD-1, CTLA-4, 2B4, and Tim-317,21,22,23,24, and/or activation of costimulatory signals from CD137 or OX4025,26,27, could rescue CD8+ T cell function during HBV infection, as evidenced by improved production of interferon (IFN)-γ and cytotoxic capacity of effector CD8+ T cells. On the other hand, CD8+ T cell response could also promote hepatic inflammatory development during acute or chronic virus infection7, as implied by clinical and animal studies28,29,30.

The co-inhibitory receptor T cell immunoglobulin and immune receptor tyrosine-based inhibitory motif domain (TIGIT), highly expressed on activated T cells, could inhibit T cell functions after engagement with its ligand CD155 on antigen-presenting cells31. Moreover, it has been demonstrated that TIGIT is a characteristic marker of exhausted CD4+ T32 and CD8+ T cells33 in tumor tissue, and enforces CD8+ T cell exhaustion during chronic lymphocytic choriomeningitis virus (LCMV) infection33. In the clinic, downregulated expression of TIGIT on both CD8+ T and CD4+ T cells were observed in hepatitis C virus (HCV) patients who were cured by direct-acting antivirals, suggesting a role for TIGIT in T cell dysfunction during HCV infection34. In addition, TIGIT expression on T cells correlated with disease progression induced by human immunodeficiency virus (HIV) or simian immunodeficiency virus (SIV) infection35,36. Nevertheless, whether TIGIT contributes to HBV-mediated immune tolerance and HBV-related HCC has not been explored.

Here, a high expression of TIGIT was found on hepatic CD8+ T cells of HBsAg transgenic (HBs-tg) mice, which are immunologically tolerant to HBV. TIGIT blockade or TIGIT deficiency could break CD8+ T cell tolerance to the viral antigen in HBs-tg mice, leading to chronic hepatitis and fibrosis. Importantly, HBsAg vaccination in combination with TIGIT blockade or TIGIT deficiency in HBs-tg mice triggered HCC development in a CD8+ T cell-dependent manner. Thus, this study has developed a mouse model of HBV-related HCC, providing experimental evidence supporting chronic inflammation in promoting cancer and revealing unfavorable consequences of the immune checkpoint blockade.

Results
TIGIT blockade or deficiency leads to chronic hepatitis
It has been demonstrated that HBs-tg mice, whose hepatocytes continuously express HBV surface antigens and adaptive immune system is tolerant to HBV, can be used as a model for HBV carriers37,38. Given that previous studies have shown that blockade of co-inhibitory receptors could restore CD8+ T cell functions in HBV-carrier people23, we explored the consequences of blocking the TIGIT pathway in the HBs-tg mouse model. HBs-tg mice were injected weekly with anti-TIGIT monoclonal antibodies (mAb) or control rat IgG (Fig. 1a). Consistent with published reports39, young HBs-tg mice had normal serum alanine aminotransferase (ALT) levels compared to wild-type (WT) mice (below 50 U/L), while elder HBs-tg mice displayed slightly elevated ALT levels (Fig. 1b). We verified the blocking efficiency by flow cytometric analysis of TIGIT staining on NK cells and CD8+ T cells from HBs-tg mice treated with anti-TIGIT mAbs (Supplementary Fig. 1a). To further confirm that the anti-TIGIT mAb is a blocking antibody rather than depleting antibody, the absolute number of peripheral blood CD8+ T cells and NK cells were counted. It was found that there was no change after antibody treatment in vivo (Supplementary Fig. 1b). In addition, flow cytometric analysis with a different clone of TIGIT antibody showed that TIGIT+ NK cells and TIGIT+CD8+ T cells were not reduced after TIGIT blockade (Supplementary Fig. 1a), confirming that the anti-TIGIT mAb injected to mice did not induce depletion of immune cells that express TIGIT. It has been reported that, when some inhibitory pathways are ablated, there will be compensatory responses induced by increased expression of other immunosuppressive receptors40. To test this possibility, we examined expression of other important inhibitory receptors, such as PD-1, CTLA-4, Tim-3, KLRG-1, and Lag-3 on CD8+ T cells and NK cells. No changes were detected after TIGIT blockade, thus excluding the potential compensatory effects of these inhibitory receptors (Supplementary Fig. 1d). Expression of CD96, a co-inhibitory receptor sharing the same ligand CD155 with TIGIT41 also remained low on CD8+ T cells after TIGIT blockade. However, it was expressed at a lower level on NK cells in TIGIT-blocked mice compared to control mice (Supplementary Fig. 1c). The co-stimulatory molecule CD226, which competes with CD96 and TIGIT for binding to CD15541, maintained a high expression on CD8+ T cells and NK cells after TIGIT blockade (Supplementary Fig. 1c).

Fig. 1

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发表于 2019-1-17 20:40 |只看该作者
肝表面抗原转基因小鼠肝细胞癌的免疫耐受性下降
吕宗、惠鹏、程孙、冯磊丽、郑美娟、陈永燕、魏海明、孙睿、田志刚
自然传播第10卷,文章编号:221(2019)下载引文

摘要

        乙肝病毒(HBV)可引起慢性炎症、肝硬化,最终导致肝细胞癌(HCC)。尽管有证据表明人类的适应性免疫与HBV相关疾病之间存在联系,但有关免疫致病机制的描述却很少。我们发现,在适应性免疫系统耐受HBsAg的转基因(HBsTG)小鼠中,作为肿瘤免疫治疗中一个有前途的免疫检查点的tigit的表达随着年龄的增长而增加。tigit阻滞或缺乏可导致慢性肝炎和纤维化,同时出现功能性HBsAg特异性细胞毒性T淋巴细胞(CTL),提示tigit阻滞或缺乏可破坏适应性免疫耐受。重要的是,在tigit阻断或缺陷的hbs-tg小鼠中,hbsag疫苗进一步以CD8+T细胞依赖性方式诱导非溶解性炎症和HCC。因此,CD8+T细胞在适应性免疫介导的肿瘤进展中起着重要作用,而TIGIT通过保持CTL的稳态平衡来维持肝脏的耐受性。

介绍

        慢性乙型肝炎病毒(HBV)感染影响着全世界超过3.5亿人,尽管年轻一代接种了有效的HBV疫苗。目前临床上的抗病毒治疗对清除病毒1几乎没有效果。积累的证据表明,慢性乙型肝炎(CHB)感染是肝细胞癌(HCC)2、3、4的重要危险因素。病毒学家将HBV介导的肝癌发生归因于病毒DNA整合到宿主DNA和癌蛋白调节X蛋白(HBX)5,6中。然而,人们越来越认识到,HBV是一种非细胞病变病毒,HBV的发病机制主要在于免疫介导的肝损伤7、8、9、10,它在没有病毒转化、插入突变和基因毒性化学物质的情况下触发了HCC的发展11。尽管取得了这些进展,但是缺乏合适的动物模型来模拟HBV相关的HCC,阻碍了对HBV诱导的HCC发展的免疫机制的研究。
        肝脏是一种独特的免疫器官,有利于诱导免疫耐受而不是免疫激活12。在CHB感染过程中,病毒特异性CD8+T细胞逐渐获得大量共抑制受体13、14、15、16的表达,如PD-1、CTLA-4和TIM-317、18。考虑到免疫介导的损伤在HBV发病机制中的作用,肝CD8+T细胞表达的共抑制受体对预防免疫驱动的病理学很重要,但也会导致CTL衰竭,从而限制病毒清除率19,20。阻断共抑制受体,如pd-1、ctla-4、2b4和tim-317、21、22、23、24和/或激活CD137或Ox4025、26、27的共刺激信号,可以在HBV感染期间挽救CD8+T细胞的功能,这可以通过改善干扰素(ifn)-γ的产生和效应器CD8+T细胞的细胞毒性能力来证明。另一方面,CD8+T细胞反应也可促进急性或慢性病毒感染7时肝脏炎症的发展,如临床和动物研究所暗示的28,29,30。
        共抑制受体T细胞免疫球蛋白和免疫受体酪氨酸基抑制基序域(tigit)在活化的T细胞上高度表达,在抗原提呈细胞31上与其配体CD155结合后能抑制T细胞功能。此外,已经证实,tigit是肿瘤组织中CD4+T32和CD8+T细胞3衰竭的特征性标志物,在慢性淋巴细胞性脉络膜原性血管炎病毒(LCMV)感染中可强制CD8+T细胞衰竭33。在临床上,通过直接作用的抗病毒药物治疗的丙型肝炎病毒(HCV)患者,在CD8+T和CD4+T细胞上观察到下调的tigit表达,提示tigit在丙型肝炎病毒感染期间T细胞功能障碍中的作用34。此外,T细胞上的tigit
        表达与人类免疫缺陷病毒(HIV)或猿免疫缺陷病毒(SIV)感染引起的疾病进展有关35,36。然而,tigit是否有助于乙肝病毒介导的免疫耐受和乙肝病毒相关的肝细胞癌尚不清楚。
        在HBsAg转基因(HBsTG)小鼠的肝CD8+T细胞中发现了高表达的tigit,该小鼠对HBV具有免疫耐受性。tigit阻滞或tigit缺乏可破坏hbs-tg小鼠对病毒抗原的CD8+T细胞耐受性,导致慢性肝炎和纤维化。重要的是,HBsAg疫苗联合tigit阻断或tigit缺乏在HBsTG小鼠中以CD8+T细胞依赖性方式触发了HCC的发展。因此,本研究建立了一个与HBV相关的HCC小鼠模型,提供了实验证据。
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