乙型肝炎病毒特异性 CD4 T 细胞反应将功能性治愈与慢性表面

StephenW

乙型肝炎病毒特异性 CD4 T 细胞反应将功能性治愈与慢性表面抗原 + 感染区分开来

    鲁本·C·霍格文
    苏珊·迪克斯特拉
    莉亚·巴奇
    亚瑟·Y·金
    利亚·刘易斯-希门尼斯
    乔治·M·劳尔
    显示所有作者

发布时间：2022年6月15日DOI：https://doi.org/10.1016/j.jhep.2022.05.041

强调

    •
    HBV 特异性 CD4 T 细胞可以直接离体分析，无需体外扩增。
    •
    与慢性感染相比，功能性 HBV 特异性 CD4 T 细胞反应在功能性治愈中更强。
    •
    MHC II 类多聚体在 HBsAg 患者中可靠地识别 HBV 特异性 CD4 T 细胞，但在存在 HBsAg 时很少。
    •
    CD4 T 细胞免疫应被视为 HBV 免疫治疗的靶点。

背景与目标
无论是否接受抗病毒治疗，很少有人能实现慢性乙型肝炎病毒 (HBV) 感染的持续功能性治愈。更好地定义介导功能性治愈的因素对于改进免疫治疗策略至关重要。我们旨在比较不同程度病毒控制患者的 HBV 特异性 T 细胞反应。
方法
我们从 124 名 HBV 感染者身上采集了血液，包括急性自限性 HBV 感染者、慢性感染者和功能性治愈的慢性感染者。我们通过 ELISpot 筛选了 HBV 特异性 T 细胞特异性，使用细胞内细胞因子染色评估了 HBV 特异性 T 细胞的功能，并使用人类白细胞抗原 (HLA) II 类四聚体染色表征了 HBV 特异性 CD4 T 细胞，所有这些都直接离体.
结果
与慢性感染中更有限的反应相比，ELISpot 筛选很容易识别急性缓解感染中的 HBV 特异性 CD4 和 CD8 T 细胞反应。与慢性感染相比，应用更灵敏的检测方法显示，功能性治愈中功能性 HBV 特异性 CD4 T 细胞的频率更高，而不是 CD8 T 细胞。与慢性感染相比，使用 HLA 多聚体的功能独立分析还发现，功能性治愈中更多的 HBV 特异性 CD4 T 细胞反应，在急性和慢性感染后都出现了 CD4 T 细胞记忆。
结论
功能性治愈与更高频率的功能性 HBV 特异性 CD4 记忆 T 细胞反应有关。因此，旨在诱导 HBV 功能性治愈的免疫治疗方法也应该旨在改善 CD4 T 细胞反应。
总结
免疫疗法是一种依赖于利用个体免疫系统的力量来针对特定疾病或病原体的治疗形式。正在为慢性 HBV 感染患者开发此类方法，以试图模拟自发控制 HBV 感染的患者的免疫反应，从而实现所谓的功能性治愈。然而，究竟是什么定义了保护性免疫反应仍不清楚。在这里，我们表明功能性治愈与 HBV 特异性 CD4 T 细胞（一种免疫细胞）的强烈反应有关。

StephenW

Hepatitis B virus-specific CD4 T cell responses differentiate functional cure from chronic surface antigen+ infection

    Ruben C. Hoogeveen
    Suzan Dijkstra
    Lea M. Bartsch
    Arthur Y. Kim
    Lia L. Lewis-Ximenez
    Georg M. Lauer
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Published:June 15, 2022DOI:https://doi.org/10.1016/j.jhep.2022.05.041

Highlights

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    HBV-specific CD4 T cells can be analysed directly ex vivo, without the need for in vitro expansion.
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    Functional HBV-specific CD4 T cell responses are stronger in functional cure vs. chronic infection.
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    MHC-class II multimers identify HBV-specific CD4 T cells reliably in HBsAg- patients, but rarely when HBsAg is present.
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    CD4 T cell immunity should be considered as a target for HBV immunotherapies.

Background & Aims
With or without antiviral treatment, few individuals achieve sustained functional cure of chronic hepatitis B virus (HBV) infection. A better definition of what mediates functional cure is essential for improving immunotherapeutic strategies. We aimed to compare HBV-specific T cell responses in patients with different degrees of viral control.
Methods
We obtained blood from 124 HBV-infected individuals, including those with acute self-limiting HBV infection, chronic infection, and chronic infection with functional cure. We screened for HBV-specific T cell specificities by ELISpot, assessed the function of HBV-specific T cells using intracellular cytokine staining, and characterized HBV-specific CD4 T cells using human leukocyte antigen (HLA) class II tetramer staining, all directly ex vivo.
Results
ELISpot screening readily identified HBV-specific CD4 and CD8 T cell responses in acute resolving infection compared with more limited reactivity in chronic infection. Applying more sensitive assays revealed higher frequencies of functional HBV-specific CD4 T cells, but not CD8 T cells, in functional cure compared to chronic infection. Function independent analysis using HLA multimers also identified more HBV-specific CD4 T cell responses in functional cure compared to chronic infection, with the emergence of CD4 T cell memory both after acute and chronic infection.
Conclusions
Functional cure is associated with higher frequencies of functional HBV-specific CD4 memory T cell responses. Thus, immunotherapeutic approaches designed to induce HBV functional cure should also aim to improve CD4 T cell responses.
Lay summary
Immunotherapy is a form of treatment that relies on harnessing the power of an individual’s immune system to target a specific disease or pathogen. Such approaches are being developed for patients with chronic HBV infection, in an attempt to mimic the immune response in patients who control HBV infection spontaneously, achieving a so-called functional cure. However, what exactly defines protective immune responses remains unclear. Herein, we show that functional cure is associated with robust responses by HBV-specific CD4 T cells (a type of immune cell).

StephenW

http://www.journal-of-hepatology.eu/article/S016882782200366X/pdf