Structure and Function of HLA-A*02-Restricted Hantaan Virus Cytotoxic T-Cell Epitope That Mediates Effective Protective Responses HLA-A2.1/Kb Transgenic Mice
Structure and Function of HLA-A*02-Restricted Hantaan Virus Cytotoxic T-Cell Epitope That Mediates Effective Protective Responses HLA-A2.1/Kb Transgenic Mice
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DOI：
10.3389/timrnu.2015.00298
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发表时间：
2016-08-08
影响因子：
7.3
通讯作者：
Jin, Boquan
中科院分区：
文献类型：
--
作者：
Ma, Ying;Cheng, Linfeng;Jin, Boquan
汉坦病毒感染会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。我们之前的研究表明，汉坦病毒（HTNV）核蛋白（NP）的CD8（+）T细胞表位aa129-aa137（FVVPILLKA，FA9）受到人类白细胞抗原（HLA）-A*02的限制，诱导了控制人类HTNV感染的特异性CDS+ T细胞反应。然而，肽FA9的体内免疫原性和FA9特异性CD8(+)T细胞免疫的作用仍不清楚。在这里，基于对肽 FA9/HLA-A*0201 复合物的详细结构分析和使用 HLA-A2.1/K-b 转基因（Tg）小鼠的功能研究，我们发现肽 FA9/HLA-A*0201 复合物的整体结构表现出典型的 MHC I 类折叠，其中 Val2 和 Ala9 作为主要锚定残基，Va13 和 Leu7 作为次要锚定残基，使肽 FA9 能够与HLA-A*0201 分子。肽FA9中部突出结合沟的残基可能是T细胞受体识别的位点。在 HLA-A2.1/Kb Tg 小鼠中用肽 FA9 进行免疫诱导了 FA9 特异性细胞毒性 T 细胞应答，其特征是诱导干扰素-γ、肿瘤坏死因子-α、颗粒酶 B 和 CD107a 高表达水平。在一项 HTNV 攻击试验中，在预接种肽 FA9 的 Tg 小鼠的肝脏、脾脏和肾脏中观察到抗原水平和 HTNV RNA 负荷显着降低。因此，我们的研究结果强调了 HTNV 表位特异性 CD8+ T 细胞免疫控制 HTNV 的能力，并支持以 HLA-A*02 限制性方式在体内自然加工的 HTNV-NP FA9 肽可能是开发 HTNV 肽疫苗的良好候选者的可能性。
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 CDS+ 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/K-b 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 Va13 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-gamma, tumor necrosis factor-alpha, 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 micepre-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.