免疫抑制检查点特征在慢性乙型肝炎抗病毒和炎症性T细胞群

StephenW

Journal of Interferon & Cytokine ResearchVol. 38, No. 7 Research Reports
Differential Expression of Immune Inhibitory Checkpoint Signatures on Antiviral and Inflammatory T Cell Populations in Chronic Hepatitis B
Helen Cooksley
, Antonio Riva
, Krum Katzarov
, Tanya Hadzhiolova-Lebeau
, Slava Pavlova
, Marieta Simonova
, Roger Williams
, and Shilpa Chokshi
Published Online:1 Jul 2018

Abstract

Virus-specific T cells are critical in mediating the pathogenesis of hepatitis B virus (HBV) infection. Interferon gamma (IFNγ)-producing T cells are associated with resolution; in contrast, interleukin-17 (IL-17)-producing T cells are linked to exacerbation of liver inflammation and injury. Checkpoint receptors stringently regulate T cell functions, with their expression profiles varying on different T cell subsets. Blockade of checkpoint receptors may be an effective therapeutic strategy for chronic hepatitis B (CHB); however, blockade may also inadvertently exacerbate proinflammatory responses. In this study, we sought to determine the balance of inflammatory and antiviral T cells and determine their inhibitory receptor profile. The frequency of total and HBV antigen-specific Th17 and Tc17 cells was higher in CHB patients compared with healthy controls (HCs). Th17 and Tc17 cells in CHB patients had significantly lower expression of T cell immunoglobulin and mucin domain protein-3 (TIM-3) compared with HCs, with no difference in programmed death-1 (PD-1) or CD244 expression. Conversely, Th1 and Tc1 cells in CHB patients hyperexpressed PD-1 and CD244, while TIM-3 expression was comparable in both cohorts. During CHB, antiviral IFNγ T cells hyperexpress multiple immune inhibitory receptors driving their functional impairment. In contrast, inflammatory Th17/Tc17 cells hypoexpress TIM-3, but not PD-1 or CD244. Checkpoint inhibitors for CHB should target PD-1 or CD244 to allow restoration of IFNγ responses without affecting inflammatory IL-17 production.

    Journal of Interferon & Cytokine Research cover image
    Volume 38Issue 7
    Jul 2018
    Information

    Copyright 2018, Mary Ann Liebert, Inc.
    To cite this article:
    Helen Cooksley, Antonio Riva, Krum Katzarov, Tanya Hadzhiolova-Lebeau, Slava Pavlova, Marieta Simonova, Roger Williams, and Shilpa Chokshi.Journal of Interferon & Cytokine Research.Jul 2018.ahead of printhttp://doi.org/10.1089/jir.2017.0109
        Published in Volume: 38 Issue 7: July 1, 2018
    Keywords
        hepatitis B virus (HBV)immune regulationinterferon gamma (IFNγ)interleukin-17 (IL-17)programmed death-1 (PD-1)T cell immunoglobulin domain and mucin domain-3 (TIM-3)checkpoint receptor inhibition
    Publication History
    Received 26 September 2017
    Accepted 14 May 2018
    Published online 1 July 2018
    Published in print 1 July 2018

StephenW

干扰素与细胞因子研究杂志Vol. 38，第7研究报告
免疫抑制检查点特征在慢性乙型肝炎抗病毒和炎症性T细胞群中的差异表达
海伦库克斯利
，Antonio Riva
，Krum Katzarov
，Tanya Hadzhiolova-Lebeau
，斯拉瓦帕夫洛娃
，Marieta Simonova
，罗杰威廉姆斯
和Shilpa Chokshi
在线发布时间：2018年7月1日

抽象

病毒特异性T细胞在介导乙型肝炎病毒（HBV）感染的发病机制中至关重要。产生干扰素γ（IFNγ）的T细胞与分辨率相关;相反，产生白细胞介素-17（IL-17）的T细胞与肝脏炎症和损伤的恶化有关。检查点受体严格调节T细胞功能，其表达谱在不同的T细胞亚群上变化。阻断检查点受体可能是慢性乙型肝炎（CHB）的有效治疗策略;然而，阻断也可能无意中加剧促炎反应。在这项研究中，我们试图确定炎症和抗病毒T细胞的平衡，并确定其抑制性受体谱。与健康对照（HC）相比，CHB患者中总HBV抗原特异性Th17和Tc17细胞的频率更高。与HC相比，CHB患者中的Th17和Tc17细胞具有显着更低的T细胞免疫球蛋白和粘蛋白结构域蛋白-3（TIM-3）的表达，程序性死亡-1（PD-1）或CD244表达没有差异。相反，CHB患者中的Th1和Tc1细胞过度表达PD-1和CD244，而两组中TIM-3表达相当。在CHB期间，抗病毒IFNγT细胞过度表达多种免疫抑制受体，导致其功能受损。相反，炎性Th17 / Tc17细胞低表达TIM-3，但不表达PD-1或CD244。用于CHB的检查点抑制剂应靶向PD-1或CD244以允许恢复IFNγ应答而不影响炎性IL-17产生。

    干扰素和细胞因子研究杂志报道图像
    第38卷第7期
    2018年7月
    信息

    版权所有2018，Mary Ann Liebert，Inc。
    引用这篇文章：
    Helen Cooksley，Antonio Riva，Krum Katzarov，Tanya Hadzhiolova-Lebeau，Slava Pavlova，Marieta Simonova，Roger Williams和Shilpa Chokshi.Journal of Interferon＆Cytokine Research.Jul 2018.ahead of printhttp：//doi.org/10.1089/jir .2017.0109
        发表于第38卷第7期：2018年7月1日
    关键词
        乙型肝炎病毒（HBV）免疫调节干扰素γ（IFNγ）白细胞介素-17（IL-17）程序性死亡-1（PD-1）T细胞免疫球蛋白结构域和粘蛋白结构域-3（TIM-3）检查点受体抑制
    出版历史
    2017年9月26日收到
    2018年5月14日接受
    在线发布2018年7月1日
    发表于2018年7月1日