Toll样受体2的预活化增强了CD8 + T细胞应答并加速了小鼠模型

StephenW

Front Immunol. 2018 Jun 29;9:1495. doi: 10.3389/fimmu.2018.01495. eCollection 2018.
Pre-Activation of Toll-Like Receptor 2 Enhances CD8+ T-Cell Responses and Accelerates Hepatitis B Virus Clearance in the Mouse Models.
Lin Y1,2,3, Huang X2,4, Wu J3, Liu J2,3, Chen M3, Ma Z2, Zhang E5, Liu Y1, Huang S3, Li Q2, Zhang X4, Hou J4, Yang D3, Lu M1,2, Xu Y1.
Author information

1
    Department of Microbiology, School of Basic Medicine, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.
2
    Institute of Virology, University Hospital of Essen, Essen, Germany.
3
    Department of Infectious Diseases, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.
4
    State Key Laboratory of Organ Failure Research, Guangdong Provincial Key Laboratory of Viral Hepatitis Research, Department of Infectious Diseases, Nanfang Hospital, Southern Medical University, Guangzhou, China.
5
    Mucosal Immunity Research Group, State Key Laboratory of Virology, Wuhan Institute of Virology, Chinese Academy of Sciences, Wuhan, China.

Abstract

Toll-like receptors (TLRs) play a crucial role in activation of innate immunity, which is essential for inducing effective adaptive immune responses. Our previous studies have shown that toll-like receptor 2 (TLR2) is required to induce effective virus-specific T-cell responses against hepatitis B virus (HBV) in vivo. However, the contribution of TLR2 activation to adaptive immunity and HBV clearance remains to be clarified. In this study, we explored the hydrodynamic injection (HI) mouse models for HBV infection and examined how the TLR2 agonist Pam3CSK (P3C) influences HBV control and modulates HBV-specific T-cell response if applied in vivo. We found that TLR2 activation by P3C injection leads to the rapid but transient production of serum proinflammatory factors interleukin-6 and tumor necrosis factor-α and activation of CD8+ T cells in vivo. Then, the anti-HBV effect and HBV-specific T-cell immunity were investigated by TLR2 activation in the mouse models for persistent or acute HBV infections using HBV plasmids pAAV-HBV1.2 and pSM2, respectively. Both P3C application at early stage and pre-activation promoted HBV clearance, while only TLR2 pre-activation enhanced HBV-specific T-cell response in the liver. In the mouse model for acute HBV infection, P3C application had no significant effect on HBV clearance though P3C significantly enhanced the HBV-specific T-cell response. Collectively, TLR2 pre-activation enhances HBV-specific T-cell responses and accelerates HBV clearance in HI mouse models. Thus, the modulation of host immune status by TLR2 agonists may be explored for immunotherapeutic strategies to control HBV infection.
KEYWORDS:

T-cell immunity; hepatitis B virus; mouse model; proinflammatory cytokines; toll-like receptor 2

PMID:
    30008718
PMCID:
    PMC6033958
DOI:
    10.3389/fimmu.2018.01495

StephenW

前免疫。 2018年6月29日; 9：1495。 doi：10.3389 / fimmu.2018.01495。 eCollection 2018。
Toll样受体2的预活化增强了CD8 + T细胞应答并加速了小鼠模型中的乙型肝炎病毒清除。
Lin Y1,2,3，Huang X2,4，Wu J3，Liu J2,3，Chen M3，Ma Z2，Zhang E5，Liu Y1，Huang S3，Li Q2，Zhang X4，Hou J4，Yang D3，Lu M1， 2，许Y1。
作者信息

1
    华中科技大学同济医学院基础医学院微生物学系，武汉
2
    德国埃森埃森大学医院病毒学研究所。
3
    华中科技大学同济医学院附属协和医院感染科，武汉
4
    南方医科大学南方医院传染病科，广东省病毒性肝炎研究重点实验室器官衰竭研究国家重点实验室，广州
五
    中国科学院武汉病毒研究所病毒学国家重点实验室粘膜免疫研究组，武汉

抽象

Toll样受体（TLR）在先天免疫的激活中起关键作用，这对于诱导有效的适应性免疫应答是必需的。我们先前的研究表明，需要Toll样受体2（TLR2）来诱导体内针对乙型肝炎病毒（HBV）的有效病毒特异性T细胞应答。然而，TLR2激活对适应性免疫和HBV清除的贡献仍有待澄清。在这项研究中，我们探索了HBV感染的水动力注射（HI）小鼠模型，并检查了TLR2激动剂Pam3CSK（P3C）如何影响HBV控制并调节HBV特异性T细胞应答（如果在体内应用）。我们发现通过P3C注射激活TLR2导致血清促炎因子白细胞介素-6和肿瘤坏死因子-α的快速但短暂的产生以及体内CD8 + T细胞的活化。然后，分别使用HBV质粒pAAV-HBV1.2和pSM2通过小鼠模型中的TLR2活化来研究抗HBV效应和HBV特异性T细胞免疫，用于持续或急性HBV感染。早期P3C应用和预激活均促进HBV清除，而只有TLR2预激活增强肝脏中HBV特异性T细胞应答。在用于急性HBV感染的小鼠模型中，P3C应用对HBV清除没有显着影响，尽管P3C显着增强HBV特异性T细胞应答。总的来说，TLR2预激活增强了HBV特异性T细胞反应并加速了HI小鼠模型中的HBV清除。因此，可以探索TLR2激动剂对宿主免疫状态的调节，以用于控制HBV感染的免疫治疗策略。
关键词：

T细胞免疫;乙型肝炎病毒;小鼠模型;促炎细胞因子; Toll样受体2

结论：
    30008718
PMCID：
    PMC6033958
DOI：
    10.3389 / fimmu.2018.01495