ILT2 表达增加导致慢性乙型肝炎病毒感染中 CD56 dim CD16 + NK 细

StephenW

ILT2 表达增加导致慢性乙型肝炎病毒感染中 CD56 dim CD16 + NK 细胞功能障碍
张英智 1 , 童世文 2 , 李世英 1 , 王学府 3 , 任宏 1 , 尹文伟 4
隶属关系
隶属关系

    1
    重庆医科大学第二附属医院传染病科病毒性肝炎研究所传染病分子生物学教育部重点实验室，重庆，400016
    2
    重庆医科大学第二附属医院临床营养科，重庆 400016
    3
    安徽医科大学药学院,安徽合肥 230032
    4
    重庆医科大学第二附属医院传染病科病毒性肝炎研究所传染病分子生物学教育部重点实验室，重庆，400016电子地址：[email protected]。

    PMID：35917968 DOI：10.1016/j.antiviral.2022.105385

抽象的

自然杀伤 (NK) 细胞在控制人类病毒感染方面发挥着至关重要的作用，但它们的活性在感染慢性乙型肝炎 (CHB) 的患者中显着受损。导致慢性乙型肝炎中 NK 细胞功能障碍的机制需要进一步阐明。在这项研究中，我们分析了来自 131 名慢性乙型肝炎患者和 36 名健康对照者的 NK 细胞上新型抑制性受体免疫球蛋白样转录物 2 (ILT2) 的表达和功能。我们观察到，与非活动携带者和对照组相比，免疫耐受、免疫活性和 HBeAg 阴性肝炎患者循环 CD56dimCD16+NK 细胞上的 ILT2 表达增加。 ILT2+CD56dimNK 细胞的频率与免疫耐受患者的血清病毒载量呈正相关。在接受抗病毒治疗的慢性乙型肝炎患者中，ILT2+CD56dimNK 细胞的百分比随着 HBV 载量而降低。功能分析表明，慢性乙型肝炎患者的 ILT2+CD56dimNK 细胞脱颗粒和 IFN-γ 产生显着减少。 ILT2 的上调与来自慢性乙型肝炎患者的 CD56dimCD16+NK 细胞的高水平凋亡相关。在一些慢性乙型肝炎患者中，ILT2 阻断可增加 CD56dimNK 细胞的细胞毒性和 IFN-γ 产生。最后，发现 ILT2 被 TGF-β1 适度上调，在免疫耐受、免疫活性和 HBeAg 阴性肝炎患者中增加。我们的研究结果表明，慢性 HBV 感染会增加 CD56dimNK 细胞上抑制性受体 ILT2 的水平并抑制其功能，为慢性乙型肝炎患者的 NK 细胞功能障碍提供了新的机制。

关键词：乙型肝炎病毒； ILT2;自然杀手； TGF-β1。

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StephenW

Increased ILT2 expression contributes to dysfunction of CD56 dim CD16 + NK cells in chronic hepatitis B virus infection
Yingzhi Zhang  1 , Shiwen Tong  2 , Shiying Li  1 , Xuefu Wang  3 , Hong Ren  1 , Wenwei Yin  4
Affiliations
Affiliations

    1
    Key Laboratory of Molecular Biology for Infectious Diseases (Ministry of Education), Institute for Viral Hepatitis, Department of Infectious Diseases, The Second Affiliated Hospital, Chongqing Medical University, Chongqing, 400016, China.
    2
    Department of Clinical Nutrition, The Second Affiliated Hospital of Chongqing Medical University, Chongqing, 400016, China.
    3
    School of Pharmacy, Anhui Medical University, Hefei, Anhui, 230032, China.
    4
    Key Laboratory of Molecular Biology for Infectious Diseases (Ministry of Education), Institute for Viral Hepatitis, Department of Infectious Diseases, The Second Affiliated Hospital, Chongqing Medical University, Chongqing, 400016, China. Electronic address: [email protected].

    PMID: 35917968 DOI: 10.1016/j.antiviral.2022.105385

Abstract

Natural killer (NK) cells play a crucial role in the control of human viral infections but their activity is significantly impaired in patients infected with chronic hepatitis B (CHB). The mechanism that contributes to NK cell dysfunction in CHB needs further elucidation. In this study, we analyzed the expression and function of the novel inhibitory receptor immunoglobulin-like transcript-2 (ILT2) on NK cells from 131 CHB patients and 36 healthy controls. We observed that ILT2 expression on circulating CD56dimCD16+NK cells was increased in immune-tolerant, immune-active and HBeAg-negative hepatitis patients compared with inactive carriers and controls. The frequency of ILT2+CD56dimNK cells was positively correlated with serum viral load in immune-tolerant patients. The percentage of ILT2+CD56dimNK cells decreased along with HBV load in CHB patients who received antiviral therapy. Functional analysis showed that ILT2+CD56dimNK cells in CHB patients had significantly reduced degranulation and IFN-γ production. Upregulation of ILT2 was associated with high levels of apoptosis in CD56dimCD16+NK cells from CHB patients. ILT2 blockade was shown to increase the cytotoxicity and IFN-γ production of CD56dimNK cells in some CHB patients. Finally, ILT2 was found to be moderately upregulated by TGF-β1, which was increased in immune-tolerant, immune-active and HBeAg-negative hepatitis patients. Our results show that chronic HBV infection increases the levels of the inhibitory receptor ILT2 on CD56dimNK cells and inhibits their functions, providing a new mechanism of NK-cell disability in CHB patients.

Keywords: Hepatitis B virus; ILT2; Natural killer; TGF-β1.

Copyright © 2022. Published by Elsevier B.V.
Conflict of interest statement

Declaration of competing interest The authors declare that they have no conflicts of interest.