TOX defines the degree of CD8+ T cell dysfunction in distinct phases of chronic HBV infection.
TOX defines the degree of CD8+ T cell dysfunction in distinct phases of chronic HBV infection.
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DOI：
10.1136/gutjnl-2020-322404
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发表时间：
2020-10-23
期刊：
影响因子：
24.5
通讯作者：
Thimme R
中科院分区：
文献类型：
--
作者：
Heim K;Binder B;Sagar;Wieland D;Hensel N;Llewellyn-Lacey S;Gostick E;Price DA;Emmerich F;Vingerhoet H;Kraft ARM;Cornberg M;Boettler T;Neumann-Haefelin C;Zehn D;Bengsch B;Hofmann M;Thimme R
慢性B型肝炎病毒（HBV）感染的特征是HBV特异性CD 8 + T细胞功能障碍，其与T细胞耗竭有关，T细胞耗竭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蛋白（TOX）被确定为CD 8 + T细胞耗竭的主要调节因子。在这里，我们讨论了TOX在HBV特异性CD 8 + T细胞功能障碍中的作用，这些功能障碍与感染的不同临床阶段有关。我们研究了来自不同HBV感染阶段的53名HLA-A*01：01、HLA-A*11：01和HLA-A*02：01阳性患者的HBV特异性CD 8 + T细胞中的TOX表达，并将其与丙型肝炎病毒（HCV）特异性、巨细胞病毒（CMV）特异性、EB病毒（EBV）特异性和流感病毒（FLU）特异性CD 8 + T细胞进行了比较。病毒特异性的CD 8 + T细胞的表型和功能分析后进行肽加载的四聚体富集和肽特异性扩增。我们的研究结果表明，HBV特异性CD 8 + T细胞中的TOX表达与慢性抗原刺激有关，与病毒载量相关，并与T细胞耗竭的表型和功能特征相关。相反，EBV特异性和CMV特异性CD 8 + T细胞中相似的TOX表达与T细胞功能障碍无关，表明不同的潜在方案。HBV特异性CD 8 + T细胞中的TOX表达也受到靶向抗原的影响，例如核心相对于聚合酶。在HBV特异性CD 8 + T细胞中，在慢性但非自限性急性HBV感染中，在自发或治疗介导的病毒控制后，TOX表达得以维持，这表明在慢性而非暂时刺激后存在永久性分子印记。我们的数据突出了TOX作为在活跃持续感染的背景下功能障碍的病毒特异性CD 8 + T细胞的特异性生物标志物。
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. 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. 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. Our data highlight TOX as biomarker specific for dysfunctional virus-specific CD8+ T cells in the context of an actively persisting infection.
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