HBV疫苗接种和HBV感染诱导HBV特异性自然杀伤细胞记忆

StephenW

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Hepatology
Original research
HBV vaccination and HBV infection induces HBV-specific natural killer cell memory

    Ratna S Wijaya1,2, http://orcid.org/0000-0001-6775-2061Scott A Read1,3,4, http://orcid.org/0000-0002-9011-4014Naomi R Truong5, Shuanglin Han1, Dishen Chen1,3, Haleh Shahidipour1,3,4, Nicole L Fewings6, Stephen Schibeci6, Mahmoud K Azardaryany1, Grant P Parnell6, David Booth6, David van der Poorten7, Rita Lin7, http://orcid.org/0000-0002-8421-5476Jacob George1,7, Mark W Douglas1,7,8, Golo Ahlenstiel1,3,4

Author affiliations

    Storr Liver Centre, The Westmead Institute for Medical Research, University of Sydney, Westmead, New South Wales, Australia
    Faculty of Medicine, Pelita Harapan University, Tangerang, Indonesia
    Blacktown Medical School, Western Sydney University, Blacktown, New South Wales, Australia
    Blacktown Hospital, Blacktown, New South Wales, Australia
    Centre for Virus Research, The Westmead Institute for Medical Research, Westmead, New South Wales, Australia
    Centre for Immunology and Allergy Research, The Westmead Institute for Medical Research, University of Sydney, Westmead, New South Wales, Australia
    Westmead Hospital, University of Sydney, Westmead, New South Wales, Australia
    Centre for Infectious Diseases and Microbiology, Marie Bashir Institute for Infectious Diseases and Biosecurity, University of Sydney at Westmead Hospital, Westmead, New South Wales, Australia

    Correspondence to Professor Golo Ahlenstiel, Western Sydney University Blacktown Mount Druitt Medical School, Blacktown, NSW 2560, Australia; [email protected]

Abstract

Objective Vaccination against hepatitis B virus (HBV) confers protection from subsequent infection through immunological memory that is traditionally considered the domain of the adaptive immune system. This view has been challenged following the identification of antigen-specific memory natural killer cells (mNKs) in mice and non-human primates. While the presence of mNKs has been suggested in humans based on the expansion of NK cells following pathogen exposure, evidence regarding antigen-specificity is lacking. Here, we demonstrate the existence of HBV-specific mNKs in humans after vaccination and in chronic HBV infection.

Design NK cell responses were evaluated by flow cytometry and ELISA following challenge with HBV antigens in HBV vaccinated, non-vaccinated and chronic HBV-infected individuals.

Results NK cells from vaccinated subjects demonstrated higher cytotoxic and proliferative responses against autologous hepatitis B surface antigen (HBsAg)-pulsed monocyte-derived dendritic cells (moDCs) compared with unvaccinated subjects. Moreover, NK cell lysis of HBsAg-pulsed moDCs was significantly higher than that of hepatitis B core antigen (HBcAg)-pulsed moDCs (non-vaccine antigen) or tumour necrosis factor α-activated moDCs in a NKG2D-dependent manner. The mNKs response was mediated by CD56dim NK cells coexpressing CD57, CD69 and KLRG1. Further, mNKs from chronic hepatitis B patients exhibited greater degranulation against HBcAg-pulsed moDCs compared with unvaccinated or vaccinated patients. Notably, mNK activity was negatively correlated with HBV DNA levels.

Conclusions Our data support the presence of a mature mNKs following HBV antigen exposure either through vaccination or infection. Harnessing these antigen specific, functionally active mNKs provides an opportunity to develop novel treatments targeting HBV in chronic infection.
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http://dx.doi.org/10.1136/gutjnl-2019-319252

StephenW

HBV疫苗接种和HBV感染诱导HBV特异性自然杀伤细胞记忆

    Ratna S Wijaya1,2，http：//orcid.org/0000-0001-6775-2061Scott A Read1,3,4，http：//orcid.org/0000-0002-9011-4014Naomi R Truong5，Shuanglin Han1，Dishen Chen1,3，Haleh Shahidipour1,3,4，Nicole L Fewings6，Stephen Schibeci6，Mahmoud K Azardaryany1，Grant P Parnell6，David Booth6，David van der Poorten7，Rita Lin7，http://orcid.org/0000-0002-8421 -5476Jacob George1,7，Mark W Douglas1,7,8，Golo Ahlenstiel1,3,4

作者单位

    澳大利亚新南威尔士州西米德市悉尼大学西米德医学研究所Storr肝脏中心
    佩里塔·哈拉潘大学医学院，印度尼西亚坦格朗
    西悉尼大学布莱克敦医学院，澳大利亚新南威尔士州布莱克敦
    澳大利亚新南威尔士州布莱克敦布莱克敦医院
    澳大利亚新南威尔士州韦斯特米德，韦斯特米德医学研究所病毒研究中心
    悉尼大学韦斯特米德医学研究所免疫学和变态反应研究中心，澳大利亚新南威尔士州韦斯特米德
    悉尼大学韦斯特米德医院，澳大利亚新南威尔士州韦斯特米德
    悉尼大学玛丽·巴希尔传染病与生物安全研究所传染病和微生物学中心，悉尼大学，新南威尔士州，韦斯特米德，韦斯特米德医院

    与西悉尼大学布莱克敦德鲁特山医学院西澳大利亚州新南威尔士州2560的Golo Ahlenstiel教授对应； [email protected]

抽象

客观的针对乙型肝炎病毒（HBV）的疫苗接种可通过传统上被认为是适应性免疫系统领域的免疫记忆来防止随后的感染。在小鼠和非人类灵长类动物中鉴定出抗原特异性记忆自然杀伤细胞（mNK）之后，这一观点受到了挑战。尽管已经基于病原体暴露后NK细胞的扩增在人类中暗示了mNK的存在，但缺乏有关抗原特异性的证据。在这里，我们证明了接种疫苗后以及慢性HBV感染者体内HBV特异性mNK的存在。

在接种，未接种和慢性感染HBV的个体中，用HBV抗原攻击后，通过流式细胞仪和ELISA评估设计的NK细胞反应。

结果与未接种疫苗的受试者相比，接种疫苗的受试者的NK细胞对自体乙型肝炎表面抗原（HBsAg）脉冲单核细胞衍生的树突状细胞（moDC）表现出更高的细胞毒性和增殖反应。此外，以NKG2D依赖的方式，HBsAg脉冲的moDC的NK细胞裂解显着高于乙肝核心抗原（HBcAg）脉冲的moDC（非疫苗抗原）或肿瘤坏死因子α激活的moDC。 mNKs反应由共表达CD57，CD69和KLRG1的CD56dim NK细胞介导。此外，与未接种疫苗或未接种疫苗的患者相比，来自慢性乙型肝炎患者的mNK表现出更大的抗HBcAg脉冲moDC脱颗粒作用。值得注意的是，mNK活性与HBV DNA水平呈负相关。

结论我们的数据支持通过疫苗接种或感染暴露于HBV抗原后存在成熟的mNKs。利用这些抗原特异的，具有功能活性的mNKs为开发针对慢性感染中HBV的新疗法提供了机会。
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http://dx.doi.org/10.1136/gutjnl-2019-319252