Immunodominant Dengue Virus-Specific CD8+ T Cell Responses Are Associated with a Memory PD-1+ Phenotype
Immunodominant Dengue Virus-Specific CD8+ T Cell Responses Are Associated with a Memory PD-1+ Phenotype
复制标题
DOI：
10.1128/jvi.02892-15
复制
发表时间：
2016-05-01
影响因子：
5.4
通讯作者：
Weiskopf, Daniela
中科院分区：
文献类型：
--
作者：
de Alwis, Ruklanthi;Bangs, Derek J.;Weiskopf, Daniela
登革热是一个主要影响热带和亚热带地区的重大公共卫生问题。对登革热病毒（DENV）防护相关因素的了解很差，这阻碍了成功研制人用疫苗。本研究旨在确定denv特异性CD8(+) T细胞的一般反应，特别是与显性反应相关的HLA等位基因的反应。在尼加拉瓜的献血者中，我们观察到HLA - B限制性反应的显著优势，特别是等位基因B* 35:01。将这些模式与斯里兰卡普通人群的模式进行比较，我们发现HLA等位基因的限制与CD8(+) T细胞反应的广度和强度之间存在很强的相关性，这表明HLA基因深刻地影响了反应的性质。大多数γ干扰素（ifn - γ）应答与效应记忆表型相关，这也在非b * 35:01表达的T细胞中检测到。然而，只有B* 35.01 denv特异性T细胞与程序性死亡1蛋白（PD-1）的显著表达相关。这些细胞不共表达其他抑制受体，并且能够在denv特异性刺激下增殖。因此，特定HLA I类等位基因的表达是影响CD8应答的幅度和广度的决定性特征，并且一种独特的、高度分化的表型与显性CD8(+) T细胞特异性相关。这些结果对疫苗设计和确定自然免疫保护的强大相关性都具有重要意义。
Dengue disease is a large public health problem that mainly afflicts tropical and subtropical regions. Understanding of the correlates of protection against dengue virus (DENV) is poor and hinders the development of a successful human vaccine. The present study aims to define DENV-specific CD8(+) T cell responses in general and those of HLA alleles associated with dominant responses in particular. In human blood donors in Nicaragua, we observed a striking dominance of HLA B-restricted responses in general and of the allele B*35: 01 in particular. Comparing these patterns to those in the general population of Sri Lanka, we found a strong correlation between restriction of the HLA allele and the breadth and magnitude of CD8(+) T cell responses, suggesting that HLA genes profoundly influence the nature of responses. The majority of gamma interferon (IFN-gamma) responses were associated with effector memory phenotypes, which were also detected in non-B*35: 01-expressing T cells. However, only the B*35: 01 DENV-specific T cells were associated with marked expression of the programmed death 1 protein (PD-1). These cells did not coexpress other inhibitory receptors and were able to proliferate in response to DENV-specific stimulation. Thus, the expression of particular HLA class I alleles is a defining characteristic influencing the magnitude and breadth of CD8 responses, and a distinct, highly differentiated phenotype is specifically associated with dominant CD8(+) T cells. These results are of relevance for both vaccine design and the identification of robust correlates of protection in natural immunity.