人乙型肝炎病毒对自然杀手和树突状细胞之间的保护性免疫

StephenW

Human hepatitis B virus negatively impacts the protective immune cross-talk between natural killer and dendritic cells
Claudia De Pasquale  1   2 , Stefania Campana  1   2 , Chiara Barberi  3 , Giacomo Sidoti Migliore  3 , Daniela Oliveri  4 , Marika Lanza  5 , Cristina Musolino  5   6 , Giovanni Raimondo  5   6 , Soldano Ferrone  7 , Teresa Pollicino  2   6 , Guido Ferlazzo  1   2   4
Affiliations
Affiliations

    1
    Laboratory of Immunology and Biotherapy, University of Messina, Messina, Italy.
    2
    Department of Human Pathology, University of Messina, Messina, Italy.
    3
    Department of Experimental Medicine (DIMES), University of Genoa, Genoa, Italy.
    4
    Cell Factory Center and Division of Clinical Pathology, University Hospital G. Martino, Messina, Italy.
    5
    Department of Clinical and Experimental Medicine, University of Messina, Messina, Italy.
    6
    Division of Clinical and Molecular Hepatology, University Hospital G. Martino, Messina, Italy.
    7
    Department of Surgery, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA.

    PMID: 33482027 DOI: 10.1002/hep.31725

Abstract

NK cells play a crucial role in the clearance of human viruses but their activity is significantly impaired in chronic hepatitis B infected patients (CHB). Cooperation with dendritic cells (DCs) is pivotal for obtaining optimal NK cell antiviral function, thus we investigated whether HBV might impact the ability of DCs to sustain NK cell functions. Human DCs were poor stimulators of IFN-γ production by NK cells when exposed to HBV, while maintained capability to trigger NK cell cytotoxicity. HBV prevented DC maturation but did not affect their expression of HLA class I, thus allowing DCs to evade NK cell lysis. Tolerogenic features of DCs exposed to HBV were further supported by their increased expression of IL-10 and immunosuppressive enzyme indoleamine-2, 3-dioxygenase that contributed to the impairment of DC-mediated NK cell IFN-γ production and proliferation respectively. HBV could also inhibit the expression of inducible immunoproteasome (iP) subunits on DCs. In fact, NK cells could induce iP subunit expression on DCs but they failed in the presence of HBV. Remarkably, circulating BDCA1+ DCs isolated from CHB patients were functionally compromised, hence altering, in turn, NK cell responses. The abnormal NK/DC interplay caused by HBV may significantly impair the efficacy of antiviral immune response in CHB patients.

Keywords: Dendritic cells; Hepatitis B virus; Immunoproteasome; Interferon-γ; Interleukin-12; Natural Killer cells.

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StephenW

人乙型肝炎病毒对自然杀手和树突状细胞之间的保护性免疫相互作用产生负面影响
克劳迪亚（Claudia De Pasquale）1 2，斯特凡妮亚·坎帕纳（Stfania Campana）1 2，奇亚拉·巴贝里（Chiara Barberi）3，贾科莫·西多蒂·米格利洛（Giacomo Sidoti Migliore）3，丹妮拉·奥利维里（Daniela Oliveri）4，马里卡·兰萨（Marika Lanza）5，克里斯蒂娜·穆索利诺（Cristina Musolino）5 6，乔瓦尼·雷蒙多（Giovanni Raimondo）5 6，索尔达诺·费罗内（Soldano Ferrone）7，特雷莎·波利奇诺（Teresa Pollicino）2 6，吉多·费拉佐（Guido Ferlazzo 1） 2 4
隶属关系
隶属关系

    1个
    意大利墨西拿墨西拿大学免疫学和生物疗法实验室。
    2
    意大利墨西拿大学墨西拿大学人类病理学系。
    3
    热那亚大学实验医学系（DIMES），意大利热那亚。
    4
    意大利墨西拿G. Martino大学医院细胞工厂中心和临床病理科。
    5
    意大利墨西拿大学墨西拿大学临床和实验医学系。
    6
    意大利墨西拿G. Martino大学医院临床和分子肝病科。
    7
    美国马萨诸塞州波士顿，哈佛医学院马萨诸塞州总医院外科。

    PMID：33482027 DOI：10.1002 / hep.31725

抽象

NK细胞在清除人类病毒中起着至关重要的作用，但在慢性乙型肝炎感染患者（CHB）中其活性明显受损。与树突状细胞（DC）的合作对于获得最佳的NK细胞抗病毒功能至关重要，因此我们研究了HBV是否会影响DC维持NK细胞功能的能力。当暴露于HBV时，人类DCs不能很好地刺激NK细胞产生IFN-γ，同时保持了触发NK细胞毒性的能力。 HBV阻止DC成熟，但不影响其HLA I类表达，从而使DC逃避NK细胞裂解。暴露于HBV的DC的致耐受性特征进一步由其IL-10和免疫抑制酶吲哚胺-2、3-二加氧酶的表达增加进一步支持，它们分别导致DC介导的NK细胞IFN-γ产生和增殖的损伤。 HBV还可以抑制DC上诱导型免疫蛋白酶体（iP）亚基的表达。实际上，NK细胞可以诱导DC上的iP亚基表达，但在HBV存在时它们会失败。值得注意的是，从CHB患者中分离出的循环BDCA1 + DC在功能上受到损害，从而改变了NK细胞的反应。 HBV引起的异常的NK / DC相互作用可能会严重削弱CHB患者的抗病毒免疫反应的功效。

关键词：树突状细胞；乙型肝炎病毒;免疫蛋白酶体;干扰素-γ；白介素12;天然杀伤细胞。

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