HBV特异性CD4 T细胞的TNF-α/ IFN-γ谱与慢性HBV感染中的肝损伤

StephenW

J Hepatol. 2019 Sep 6. pii: S0168-8278(19)30517-3. doi: 10.1016/j.jhep.2019.08.024. [Epub ahead of print]
TNF-α/IFN-γ profile of HBV-specific CD4 T cells is associated with liver damage and viral clearance in chronic HBV infection.
Wang H1, Luo H1, Wan X1, Fu X2, Mao Q1, Xiang X1, Zhou Y1, He W1, Zhang J1, Guo Y1, Tan W3, Deng G4.
Author information

1
    Department of Infectious Diseases, Southwest Hospital, Third Military Medical University (Army Medical University), Chongqing 400038, China.
2
    Institute of Immunology, Third Military Medical University (Army Medical University), Chongqing 400038, China.
3
    Department of Infectious Diseases, Southwest Hospital, Third Military Medical University (Army Medical University), Chongqing 400038, China. Electronic address: [email protected].
4
    Department of Infectious Diseases, Southwest Hospital, Third Military Medical University (Army Medical University), Chongqing 400038, China. Electronic address: [email protected].

Abstract
BACKGROUND & AIMS:

The role of Hepatitis B virus (HBV)-specific CD4 T cells in chronic HBV infection patients is not clear.
METHODS:

Through intracellular IFN-γ and TNF-α staining, HBV-specific CD4 T cells were analyzed in 68 chronic HBV infection patients with alanine aminotransferase (ALT) < 2×upper limit of normal (ULN) and 28 hepatitis B flare patients. HBV-specific HLA-DRB1*0803/HLA-DRB1*1202-restricted CD4 T-cell epitopes were identified.
RESULTS:

TNF-α producing cells were the dominant population in patients' HBV-specific CD4 T cells. In patients with ALT < 2×ULN, both the frequency and the dominance of HBV-specific IFN-γ producing CD4 T cells increased sequentially in patients with elevated levels of viral clearance: HBeAg positive, HBeAg negative, and HBsAg negative. In hepatitis B flare patients, the frequency of HBV core-specific TNF-α producing CD4 T cells was positively correlated with patients' ALT and total bilirubin level, and the frequency of those cells changed in parallel with the severity of liver damage. Patients with HBeAg/HBsAg loss after flare showed higher frequency and dominance of HBV-specific IFN-γ producing CD4 T cells, compared to patients without HBeAg/HBsAg loss. Both the frequency and the dominance of HBV S-specific IFN-γ producing CD4 T cells were positively correlated with the decrease of HBsAg during flare. A differentiation process from TNF-α producing cell to IFN-γ producing cell in HBV-specific CD4 T cells was observed during flare. Eight and 9 HBV-derived peptides/pairs were identified as HLA-DRB1*0803 restricted epitopes and HLA-DRB1*1202 restricted epitopes, respectively.
CONCLUSIONS:

HBV-specific TNF-α producing CD4 T cells is associated with liver damage, while HBV-specific IFN-γ producing CD4 T cells is associated with viral clearance in chronic HBV infection patients.
LAY SUMMARY:

TNF-α producing cells are the dominant population of HBV-specific CD4 T cells in chronic HBV infection patients, and this population might contribute to the aggravation of liver damage in hepatitis B flare patients. HBV-specific IFN-γ producing CD4 T cells are associated with HBV viral clearance. Differentiation from HBV-specific TNF-α producing CD4 T cells into HBV-specific IFN-γ producing CD4 T cells might favor HBV viral clearance.

Copyright © 2019. Published by Elsevier B.V.
KEYWORDS:

CD4 T cells; Hepatitis B virus; epitope; liver damage; viral clearance

PMID:
    31499130
DOI:
    10.1016/j.jhep.2019.08.024

StephenW

J Hepatol。 2019年9月6日.pii：S0168-8278（19）30517-3。 doi：10.1016 / j.jhep.2019.08.024。 [印刷前的电子版]
HBV特异性CD4 T细胞的TNF-α/ IFN-γ谱与慢性HBV感染中的肝损伤和病毒清除有关。
Wang H1，Luo H1，Wan X1，Fu X2，Mao Q1，Xiang X1，Zhou Y1，He W1，Zhang J1，Guo Y1，Tan W3，Deng G4。
作者信息

1
    第三军医大学西南医院感染科（军医大学），重庆400038
2
    第三军医大学免疫学研究所（陆军医科大学），重庆400038
3
    第三军医大学西南医院感染科（军医大学），重庆400038电子地址：[email protected]。
4
    第三军医大学西南医院感染科（军医大学），重庆400038电子地址：[email protected]。

抽象
背景与目的：

乙型肝炎病毒（HBV）特异性CD4 T细胞在慢性HBV感染患者中的作用尚不清楚。
方法：

通过细胞内IFN-γ和TNF-α染色，分析了68例丙型氨基转移酶（ALT）<2×正常上限（ULN）和28例乙型肝炎患者的慢性HBV感染患者的HBV特异性CD4 T细胞。鉴定了HBV特异性HLA-DRB1 * 0803 / HLA-DRB1 * 1202限制性CD4 T细胞表位。
结果：

产生TNF-α的细胞是患者HBV特异性CD4 T细胞的主要群体。在ALT <2×ULN的患者中，HBV特异性IFN-γ产生CD4 T细胞的频率和优势在病毒清除水平升高的患者中依次增加：HBeAg阳性，HBeAg阴性和HBsAg阴性。在乙型肝炎病毒中，HBV核心特异性TNF-α产生CD4 T细胞的频率与患者的ALT和总胆红素水平呈正相关，并且这些细胞的频率与肝损伤的严重程度相关。与没有HBeAg / HBsAg消失的患者相比，发作后HBeAg / HBsAg消失的患者表现出HBV特异性IFN-γ产生CD4 T细胞的频率和优势。产生HBV S特异性IFN-γ的CD4 T细胞的频率和优势与发作期间HBsAg的降低呈正相关。在耀斑期间观察到从产生TNF-α的细胞到HBV特异性CD4T细胞中产生IFN-γ的细胞的分化过程。 8和9个HBV衍生的肽/对分别被鉴定为HLA-DRB1 * 0803限制性表位和HLA-DRB1 * 1202限制性表位。
结论：

产生HBV特异性TNF-α的CD4 T细胞与肝损伤有关，而产生HBV特异性IFN-γ的CD4 T细胞与慢性HBV感染患者的病毒清除有关。
LAY总结：

产生TNF-α的细胞是慢性HBV感染患者中HBV特异性CD4 T细胞的主要群体，并且该群体可能导致乙型肝炎突发病人肝损伤的加重。产生HBV特异性IFN-γ的CD4 T细胞与HBV病毒清除有关。从产生HBV特异性TNF-α的CD4T细胞分化成HBV特异性产生IFN-γ的CD4T细胞可能有利于HBV病毒清除。

版权所有©2019。Elsevier B.V.
关键词：

CD4 T细胞;乙型肝炎病毒;表位;肝损害;病毒清除

结论：
    31499130
DOI：
    10.1016 / j.jhep.2019.08.024