Immunodominant West Nile Virus T Cell Epitopes Are Fewer in Number and Fashionably Late.
Immunodominant West Nile Virus T Cell Epitopes Are Fewer in Number and Fashionably Late.
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DOI：
10.4049/jimmunol.1501821
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发表时间：
2016-05-15
期刊：
影响因子：
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通讯作者：
Hildebrand WH
中科院分区：
文献类型：
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作者：
Kaabinejadian S;McMurtrey CP;Kim S;Jain R;Bardet W;Schafer FB;Davenport JL;Martin AD;Diamond MS;Weidanz JA;Hansen TH;Hildebrand WH
I 类人类白细胞抗原 (HLA) 通过在细胞表面呈递病原体编码的肽来标记受感染的细胞以进行免疫靶向。受感染细胞特有的病毒肽的表征对于理解 CD8+ T 细胞反应和开发基于 T 细胞的免疫疗法非常重要。之前报道了 HLA-A*02:01 自然呈递的一系列西尼罗病毒 (WNV) 表位，在此我们针对其中三种肽/HLA 复合物（免疫显性 SVG9（E 蛋白）、次显性 SLF9（NS4B 蛋白）和免疫隐性 YTM9（NS3 蛋白））生成了 T 细胞受体模拟单克隆抗体 (TCRm mAb)，并使用这些 TCRm mAb 进行染色WNV 感染的细胞系和初级抗原呈递细胞。 WNV 感染细胞的 TCRm 染色表明，免疫隐性 YTM9 比更具免疫原性的 SLF9 和 SVG9 配体出现早几个小时，密度高 5 至 10 倍。此外，抑制与抗原加工（TAP）相关的转运蛋白后的染色表明，尽管源自不同的细胞区室，但所有三种病毒配体均以 TAP 依赖性方式呈递。这项研究首次使用 TCRm mAb 来定义由一种病毒编码的一系列表位的 HLA 呈递动力学和强度，结果描绘了一种模式，其中各个表位在丰度和可用性方面存在显着差异。观察到免疫显性配体可以在较低水平和感染后较晚的时间点被发现，这表明可能有必要重新评估影响 T 细胞反应性的因素。
Class I Human Leukocyte Antigens (HLA) mark infected cells for immune targeting by presenting pathogen encoded peptides on the cell surface. Characterization of viral peptides unique to infected cells is important for understanding CD8+ T cell responses and for the development of T cell-based immunotherapies. Having previously reported a series of West Nile virus (WNV) epitopes that are naturally presented by HLA-A*02:01, here we generated T cell receptor mimic monoclonal antibodies (TCRm mAbs) to three of these peptide/HLA complexes - the immunodominant SVG9 (E protein), the subdominant SLF9 (NS4B protein), and the immunorecessive YTM9 (NS3 protein) - and used these TCRm mAbs to stain WNV infected cell lines and primary antigen presenting cells. TCRm staining of WNV infected cells demonstrated that the immunorecessive YTM9 appeared several hours earlier and at 5 to 10 fold greater density than the more immunogenic SLF9 and SVG9 ligands. Moreover, staining following inhibition of the transporter associated with antigen processing (TAP) demonstrated that all three viral ligands were presented in a TAP-dependent manner despite originating from different cellular compartments. This study represents the first use of TCRm mAbs to define the kinetics and magnitude of HLA presentation for a series of epitopes encoded by one virus, and the results depict a pattern whereby individual epitopes differ considerably in abundance and availability. The observation that immunodominant ligands can be found at lower levels and at later time points post-infection suggests that a reevaluation of the factors that combine to shape T cell reactivity may be warranted.