TOX定义了慢性HBV感染不同阶段CD8 + T细胞功能障碍的程度

StephenW

TOX defines the degree of CD8+ T cell dysfunction in distinct phases of chronic HBV infection
Kathrin Heim  1   2 , Benedikt Binder  1 , Sagar  1 , Dominik Wieland  1 , Nina Hensel  1   2 , Sian Llewellyn-Lacey  3 , Emma Gostick  3 , David A Price  3   4 , Florian Emmerich  5 , Hildegard Vingerhoet  6 , Anke R M Kraft  7   8 , Markus Cornberg  8   9 , Tobias Boettler  1 , Christoph Neumann-Haefelin  1 , Dietmar Zehn  10 , Bertram Bengsch  1   11 , Maike Hofmann  12 , Robert Thimme  12
Affiliations
Affiliations

    1
    Internal Medicine II, Faculty of Medicine, Freiburg University Hospital, Freiburg, Germany.
    2
    Faculty of Biology, University of Freiburg, Freiburg, Germany.
    3
    Division of Infection and Immunity, Cardiff University School of Medicine, Cardiff, UK.
    4
    Systems Immunity Research Institute, Cardiff University School of Medicine, Cardiff, UK.
    5
    Institute for Transfusion Medicine and Gene Therapy, Factulty of Medicine, Freiburg University Hospital, Freiburg, Germany.
    6
    Internal Medicine II, Freiburg University Hospital, Freiburg, Germany.
    7
    Department of Gastroenterology, Hepatology and Endocrinology, Hannover Medical School, Hannover, Niedersachsen, Germany.
    8
    German Centre for Infection Research Association, Braunschweig, Germany.
    9
    Department of Gastroenterology, Hepatology and Endocrinology, Centre for individualised Infection Medicine (CiiM), Hannover Medical School, Hannover, Germany.
    10
    Division of Animal Physiology and Immunology, School of Life Sciences Weihenstephan, Technical University of Munich, Munich, Germany.
    11
    Signalling Research Centres BIOSS and CIBSS, University of Freiburg, Freiburg, Germany.
    12
    Internal Medicine II, Faculty of Medicine, Freiburg University Hospital, Freiburg, Germany [email protected] [email protected].

    PMID: 33097558 DOI: 10.1136/gutjnl-2020-322404

Abstract

Objective: Chronic hepatitis B virus (HBV) infection is characterised by HBV-specific CD8+ T cell dysfunction that has been linked to Tcell exhaustion, a distinct differentiation programme associated with persisting antigen recognition. Recently, Thymocyte Selection-Associated High Mobility Group Box (TOX) was identified as master regulator of CD8+ T cell exhaustion. Here, we addressed the role of TOX in HBV-specific CD8+ T cell dysfunction associated with different clinical phases of infection.

Design: We investigated TOX expression in HBV-specific CD8+ T cells from 53 HLA-A*01:01, HLA-A*11:01 and HLA-A*02:01 positive patients from different HBV infection phases and compared it to hepatitis C virus (HCV)-specific, cytomegalovirus (CMV)-specific, Epstein-Barr virus (EBV)-specific and influenza virus (FLU)-specific CD8+ T cells. Phenotypic and functional analyses of virus-specific CD8+ T cells were performed after peptide-loaded tetramer-enrichment and peptide-specific expansion.

Results: Our results show that TOX expression in HBV-specific CD8+ T cells is linked to chronic antigen stimulation, correlates with viral load and is associated with phenotypic and functional characteristics of T-cell exhaustion. In contrast, similar TOX expression in EBV-specific and CMV-specific CD8+ T cells is not linked to T-cell dysfunction suggesting different underlying programmes. TOX expression in HBV-specific CD8+ T cells is also affected by targeted antigens, for example, core versus polymerase. In HBV-specific CD8+ T cells, TOX expression is maintained after spontaneous or therapy-mediated viral control in chronic but not self-limiting acute HBV infection indicating a permanent molecular imprint after chronic but not temporary stimulation.

Conclusion: Our data highlight TOX as biomarker specific for dysfunctional virus-specific CD8+ T cells in the context of an actively persisting infection.

Keywords: T lymphocytes; chronic viral hepatitis; hepatitis B; immune response.

© Author(s) (or their employer(s)) 2020. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.

StephenW

TOX定义了慢性HBV感染不同阶段CD8 + T细胞功能障碍的程度
凯瑟琳·海姆（Kathrin Heim）1 2，贝尼迪克特（Benedikt Binder）1，萨加尔（Sagar）1，多米尼克·维兰（Dominik Wieland）1，尼娜·亨塞尔（Nina Hensel）1 2，辛安·勒韦林·莱西（Sian Llewellyn-Lacey）3，艾玛·戈德（Emma Gostick）3，大卫·阿·普莱斯（David A Price）3 4，弗洛里安·艾默里奇（Florian Emmerich）5，希尔德加·温格霍特（Hildegard Vingerhoet）6，安克·卡夫（Anke RM Kraft）7 8 ，Markus Cornberg 8 9，Tobias Boettler 1，Christoph Neumann-Haefelin 1，Dietmar Zehn 10，Bertram Bengsch 1 11，Maike Hofmann 12，Robert Thimme 12
隶属关系
隶属关系

    1个
    德国弗莱堡大学附属弗莱堡大学医学院内科II。
    2
    弗莱堡大学生物系，德国弗莱堡。
    3
    英国加的夫加的夫大学医学院感染与免疫学系。
    4
    英国加的夫加的夫大学医学院系统免疫研究所。
    5
    德国弗莱堡大学附属弗赖堡大学医院输血医学与基因治疗研究所。
    6
    德国弗莱堡弗莱堡大学医院内科II。
    7
    汉诺威医学院胃肠病学，肝病学和内分泌学系，德国下萨克森州汉诺威。
    8
    德国感染研究协会中心，德国不伦瑞克。
    9
    德国汉诺威医学院，汉诺威医学院消化病学，肝病学和内分泌学系，个体感染医学中心（CiiM）。
    10
    慕尼黑工业大学生命科学学院动物生理学和免疫学系，德国慕尼黑。
    11
    信号研究中心BIOSS和CIBSS，德国弗莱堡大学。
    12
    德国弗赖堡弗莱堡大学医院内科II，医学博士[email protected] [email protected]。

    PMID：33097558 DOI：10.1136 / gutjnl-2020-322404

抽象

目的：慢性乙型肝炎病毒（HBV）感染的特征是HBV特异性CD8 + T细胞功能异常，与T细胞衰竭有关，这是一种与持续抗原识别相关的独特分化程序。最近，胸腺细胞选择相关的高迁移率族盒（TOX）被确定为CD8 + T细胞衰竭的主要调节剂。在这里，我们探讨了TOX在与感染的不同临床阶段相关的HBV特异性CD8 + T细胞功能障碍中的作用。

设计：我们调查了来自不同HBV感染阶段的53例HLA-A * 01：01，HLA-A * 11：01和HLA-A * 02：01阳性患者的HBV特异性CD8 + T细胞中的TOX表达，并将其与肝炎进行了比较C病毒（HCV）特定，巨细胞病毒（CMV）特定，爱泼斯坦-巴尔病毒（EBV）特定和流感病毒（FLU）特定CD8 + T细胞。载有肽的四聚体富集和肽特异性扩增后，进行了病毒特异性CD8 + T细胞的表型和功能分析。

结果：我们的结果表明，HBV特异性CD8 + T细胞中的TOX表达与慢性抗原刺激相关，与病毒载量相关，并且与T细胞衰竭的表型和功能特征有关。相反，在EBV特异性和CMV特异性CD8 + T细胞中类似的TOX表达与T细胞功能障碍没有联系，表明存在不同的基础程序。 HBV特异性CD8 + T细胞中的TOX表达也受到靶向抗原的影响，例如核心酶与聚合酶​​。在HBV特异性CD8 + T细胞中，在慢性或非自限性急性HBV感染中，自发或由治疗介导的病毒控制后，TOX的表达得以维持，这表明慢性但非暂时性刺激后具有永久性分子烙印。

结论：我们的数据强调了在积极持续感染的情况下，TOX是功能异常的病毒特异性CD8 + T细胞特有的生物标志物。

关键词：T淋巴细胞； T淋巴细胞慢性病毒性肝炎乙型肝炎；免疫反应。

©2020年作者（或其雇主）。CCBY-NC允许重复使用。禁止商业重复使用。查看权限。由BMJ发布。

StephenW

https://gut.bmj.com/content/gutj ... 020-322404.full.pdf