T Cell Responses Induced by Attenuated Flavivirus Vaccination Are Specific and Show Limited Cross-Reactivity with Other Flavivirus Species
T Cell Responses Induced by Attenuated Flavivirus Vaccination Are Specific and Show Limited Cross-Reactivity with Other Flavivirus Species
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DOI：
10.1128/jvi.00089-20
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发表时间：
2020-05-01
影响因子：
5.4
通讯作者：
Sette, Alessandro
中科院分区：
文献类型：
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作者：
Grifoni, Alba;Voic, Hannah;Sette, Alessandro
黄病毒属的成员具有高度的序列相似性，并且经常在相同的地理区域传播。然而，由一种病毒物种诱导的T细胞是否与其他相关黄病毒交叉反应尚未得到全球性解决。在这项研究中，我们使用自然暴露于DENV或用DENV（TV 005）或YF 17 D疫苗免疫的个体的外周血单核细胞（PBMC）通过细胞内细胞因子染色（ICS）测试了源自登革热（DENV）、寨卡（ZIKV）、日本脑炎（JEV）、西尼罗河（WNV）和黄热病（YFV）病毒的表位库。CD 8 T细胞应答识别来自多种黄病毒的表位;然而，交叉反应性应答的幅度始终比自体表位池低几倍，并且与活化标志物（如CD 40 L、CD 69和CD 137）的较低表达相关。接下来，我们表征了代表29种不同个体表位/供体组合的短期T细胞系（TCL）的抗原敏感性。来源于DENV单价疫苗的TCL诱导了在DENV血清复合物内交叉反应的CD 8和CD 4 T细胞，但对于大多数其他黄病毒，其抗原敏感性始终与>100倍的低抗原敏感性相关，没有YFV衍生肽的交叉识别。来自YF 17 D疫苗接种者的CD 8和CD 4 TCL与任何其他黄病毒的交叉反应性非常有限，并且在八个病例中有五个病例的抗原敏感性低于1,000倍。总的来说，我们的数据表明有限的交叉反应，为CD 4和CD 8 T细胞之间的黄病毒的反应，并了解自然感染引起的免疫和战略，以开发活减毒疫苗对黄病毒species.IMPORTANCE的信封（E）蛋白是主要目标的中和抗体登革热病毒（DENV）和黄热病病毒（YFV）。因此，几种DENV疫苗构建体以活减毒疫苗形式使用E蛋白，利用来源于异源黄病毒（例如YF）的骨架作为递送载体。该骨架包含非结构（NS）和衣壳（C）抗原，它们是T细胞应答的主要靶标。在这里，我们证明，尽管序列同源性很高，但不同黄病毒之间T细胞反应水平上的交叉反应性非常有限。因此，使用异源黄病毒属作为减毒活疫苗载体不太可能产生最佳T细胞应答，因此可能损害疫苗性能。
Members of the flavivirus genus share a high level of sequence similarity and often circulate in the same geographical regions. However, whether T cells induced by one viral species cross-react with other related flaviviruses has not been globally addressed. In this study, we tested pools of epitopes derived from dengue (DENV), Zika (ZIKV), Japanese encephalitis (JEV), West Nile (WNV), and yellow fever (YFV) viruses by intracellular cytokine staining (ICS) using peripheral blood mononuclear cells (PBMCs) of individuals naturally exposed to DENV or immunized with DENV (TV005) or YF17D vaccine. CD8 T cell responses recognized epitopes from multiple flaviviruses; however, the magnitude of cross-reactive responses was consistently severalfold lower than those to the autologous epitope pools and was associated with lower expression of activation markers such as CD40L, CD69, and CD137. Next, we characterized the antigen sensitivity of short-term T cell lines (TCL) representing 29 different individual epitope/donor combinations. TCL derived from DENV monovalent vaccinees induced CD8 and CD4 T cells that cross-reacted within the DENV serocomplex but were consistently associated with >100-fold-lower antigen sensitivity for most other flaviviruses, with no cross-recognition of YFV-derived peptides. CD8 and CD4 TCL from YF17D vaccinees were associated with very limited cross-reactivity with any other flaviviruses and in five out of eight cases >1,000-fold-lower antigen sensitivity. Overall, our data suggest limited cross-reactivity for both CD4 and CD8 T cell responses between flaviviruses and have implications for understanding immunity elicited by natural infection and strategies to develop live attenuated vaccines against flaviviral species.IMPORTANCE The envelope (E) protein is the dominant target of neutralizing antibodies for dengue virus (DENV) and yellow fever virus (YFV). Accordingly, several DENV vaccine constructs use the E protein in a live attenuated vaccine format, utilizing a backbone derived from a heterologous flavivirus (such as YF) as a delivery vector. This backbone comprises the nonstructural (NS) and capsid (C) antigens, which are dominant targets of T cell responses. Here, we demonstrate that cross-reactivity at the level of T cell responses among different flaviviruses is very limited, despite high levels of sequence homology. Thus, the use of heterologous flavivirus species as a live attenuated vaccine vector is not likely to generate optimal T cell responses and might thus impair vaccine performance.