Human CD8+ T-Cell Responses Against the 4 Dengue Virus Serotypes Are Associated With Distinct Patterns of Protein Targets.
Human CD8+ T-Cell Responses Against the 4 Dengue Virus Serotypes Are Associated With Distinct Patterns of Protein Targets.
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DOI：
10.1093/infdis/jiv289
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发表时间：
2015-12
期刊：
影响因子：
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通讯作者：
D. Weiskopf;Cristhiam Cerpas;Michael A. Angelo;Derek J. Bangs;J. Sidney;S. Paul;Bjoern Peters;Françoise P Sanches;Cassia G T Silvera;P. R. Costa;E. Kallás;L. Gresh;A. D. de Silva;Á. Balmaseda;E. Harris;A. Sette
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文献类型：
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作者：
D. Weiskopf;Cristhiam Cerpas;Michael A. Angelo;Derek J. Bangs;J. Sidney;S. Paul;Bjoern Peters;Françoise P Sanches;Cassia G T Silvera;P. R. Costa;E. Kallás;L. Gresh;A. D. de Silva;Á. Balmaseda;E. Harris;A. Sette
所有4种登革病毒（DENV）血清型现在同时在全世界传播，并且每年造成多达4亿人感染。以前在HLA转基因小鼠和人类疫苗接种者中对CD8（+）T细胞应答的研究表明，结构蛋白与非结构蛋白之间的免疫优势等级随着感染血清型的不同而不同。这导致了一种假设，即CD8（+）T细胞应答的表型特异性反应性存在内在差异。方法：我们通过分析来自斯里兰卡和尼加拉瓜的自然感染的人类供体中的T细胞型特异性CD8（+）T细胞反应性，使用体外干扰素γ特异性酶联免疫吸附斑点试验来验证这一假设。结果在两个队列中鉴定出了显著相似和明确的免疫优势型特异性模式。在两个队列中占干扰素γ应答90%的表位合并产生了全局表位库。其反应性在巴西自然感染的供体中得到证实，证明了其全球适用性。结论本研究为DENV蛋白的不同亚型特异性免疫原性提供了新的认识。它进一步提供了一个潜在的有价值的工具，用于未来的研究CD8（+）T细胞反应，在典型的小样本体积可从急性发热患者和儿童，而不需要事先知道感染DENV血清型或HLA型。
BACKGROUND All 4 dengue virus (DENV) serotypes are now simultaneously circulating worldwide and responsible for up to 400 million human infections each year. Previous studies of CD8(+) T-cell responses in HLA-transgenic mice and human vaccinees demonstrated that the hierarchy of immunodominance among structural versus nonstructural proteins differs as a function of the infecting serotype. This led to the hypothesis that there are intrinsic differences in the serotype-specific reactivity of CD8(+) T-cell responses. METHODS We tested this hypothesis by analyzing serotype-specific CD8(+) T-cell reactivity in naturally infected human donors from Sri Lanka and Nicaragua, using ex vivo interferon γ-specific enzyme-linked immunosorbent spot assays. RESULTS Remarkably similar and clear serotype-specific patterns of immunodominance in both cohorts were identified. Pooling of epitopes that accounted for 90% of the interferon γ response in both cohorts resulted in a global epitope pool. Its reactivity was confirmed in naturally infected donors from Brazil, demonstrating its global applicability. CONCLUSIONS This study provides new insight into differential serotype-specific immunogenicity of DENV proteins. It further provides a potentially valuable tool for future investigations of CD8(+) T-cell responses in the typically small sample volumes available from patients with acute fever and children without requiring prior knowledge of either infecting DENV serotype or HLA type.