Structure and Function of HLA-A*02-Restricted Hantaan Virus Cytotoxic T-Cell Epitope That Mediates Effective Protective Responses in HLA-A2.1/K(b) Transgenic Mice.
Structure and Function of HLA-A*02-Restricted Hantaan Virus Cytotoxic T-Cell Epitope That Mediates Effective Protective Responses in HLA-A2.1/K(b) Transgenic Mice.
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DOI：
10.3389/fimmu.2016.00298
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发表时间：
2016
影响因子：
7.3
通讯作者：
Jin B
中科院分区：
文献类型：
--
作者：
Ma Y;Cheng L;Yuan B;Zhang Y;Zhang C;Zhang Y;Tang K;Zhuang R;Chen L;Yang K;Zhang F;Jin B
汉坦病毒感染引起人类严重的新发疾病，并与高死亡率相关;因此，它们已成为全球公共卫生问题。我们以前的研究表明，汉滩病毒（HTNV）核蛋白（NP）的CD 8 + T细胞表位aa 129-aa 137（FVVPILLKA，FA 9），受人类白细胞抗原（HLA）-A*02限制，诱导特异性CD 8 + T细胞应答，控制HTNV在人类中的感染。然而，肽FA 9的体内免疫原性和FA 9特异性CD 8 + T细胞免疫的作用仍不清楚。在此，基于肽FA 9/HLA-A*0201复合物的详细结构分析和使用HLA-A2.1/Kb转基因（Tg）小鼠的功能研究，我们发现FA 9/HLA-A* 肽的整体结构0201复合物显示典型的MHC I类折叠，其中Val 2和Ala 9作为主要锚残基，Val 3和Leu 7作为允许肽FA 9结合的次要锚残基与HLA-A*0201分子紧密结合。肽FA 9的中间部分中的从结合沟突出的残基可能是允许被T细胞受体识别的位点。在HLA-A2.1/K B Tg小鼠中用肽FA 9免疫诱导FA 9特异性细胞毒性T细胞应答，其特征在于诱导高水平的干扰素-γ、肿瘤坏死因子-α、颗粒酶B和CD 107 a表达。在HTNV攻击试验中，在用肽FA 9预接种的Tg小鼠的肝、脾和肾中观察到抗原和HTNV RNA载量的水平显著降低。因此，我们的研究结果突出了HTNV表位特异性CD 8 + T细胞免疫控制HTNV的能力，并支持HTNV-NP FA 9肽（以HLA-A*02限制性方式在体内天然加工）可能是开发HTNV肽疫苗的良好候选物的可能性。
Hantavirus infections cause severe emerging diseases in humans and are associated with high mortality rates; therefore, they have become a global public health concern. Our previous study showed that the CD8+ T-cell epitope aa129–aa137 (FVVPILLKA, FA9) of the Hantaan virus (HTNV) nucleoprotein (NP), restricted by human leukocyte antigen (HLA)-A*02, induced specific CD8+ T-cell responses that controlled HTNV infection in humans. However, the in vivo immunogenicity of peptide FA9 and the effect of FA9-specific CD8+ T-cell immunity remain unclear. Here, based on a detailed structural analysis of the peptide FA9/HLA-A*0201 complex and functional investigations using HLA-A2.1/Kb transgenic (Tg) mice, we found that the overall structure of the peptide FA9/HLA-A*0201 complex displayed a typical MHC class I fold with Val2 and Ala9 as primary anchor residues and Val3 and Leu7 as secondary anchor residues that allow peptide FA9 to bind tightly with an HLA-A*0201 molecule. Residues in the middle portion of peptide FA9 extruding out of the binding groove may be the sites that allow for recognition by T-cell receptors. Immunization with peptide FA9 in HLA-A2.1/Kb Tg mice induced FA9-specific cytotoxic T-cell responses characterized by the induction of high expression levels of interferon-γ, tumor necrosis factor-α, granzyme B, and CD107a. In an HTNV challenge trial, significant reductions in the levels of both the antigens and the HTNV RNA loads were observed in the liver, spleen, and kidneys of Tg mice pre-vaccinated with peptide FA9. Thus, our findings highlight the ability of HTNV epitope-specific CD8+ T-cell immunity to control HTNV and support the possibility that the HTNV-NP FA9 peptide, naturally processed in vivo in an HLA-A*02-restriction manner, may be a good candidate for the development HTNV peptide vaccines.