人类乙型肝炎病毒会对自然杀手和树突状细胞之间的保护性

StephenW

Human hepatitis B virus negatively impacts the protective immune cross‐talk between natural killer and dendritic cells
Claudia De Pasquale
Stefania Campana
Chiara Barberi
Giacomo Sidoti Migliore
Daniela Oliveri
Marika Lanza
Cristina Musolino
Giovanni Raimondo
Soldano Ferrone
… See all authors
First published: 22 January 2021
https://doi.org/10.1002/hep.31725

This article has been accepted for publication and undergone full peer review but has not been through the copyediting, typesetting, pagination and proofreading process, which may lead to differences between this version and the Version of Record. Please cite this article as doi:10.1002/hep.31725
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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.

StephenW

人类乙型肝炎病毒会对自然杀手和树突状细胞之间的保护性免疫干扰产生负面影响
克劳迪娅·德·帕斯夸莱
斯特凡娜·坎帕纳（Stefania Campana）
奇亚拉·巴贝里（Chiara Barberi）
贾科莫·西多（Giacomo Sidoti Migliore）
丹妮拉（Daniela Oliveri）
玛丽卡·兰扎（Marika Lanza）
克里斯蒂娜·穆索利诺（Cristina Musolino）
乔凡尼·雷蒙多（Giovanni Raimondo）
索尔达诺·佛罗内（Soldano Ferrone）
…查看所有作者
首次发布：2021年1月22日
https://doi.org/10.1002/hep.31725

本文已被接受发表，并且经过了完整的同行评审，但尚未经过复制编辑，排版，分页和校对过程，这可能会导致此版本与“记录版本”之间存在差异。请引用本文作为doi：10.1002 / hep.31725
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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-双加氧酶的表达增加进一步支持，分别导致DC介导的NK细胞IFN-γ产生和增殖受损。 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损害CHB患者的抗病毒免疫反应的功效。