Single-cell analysis reveals divergent responses of human dendritic cells to the MVA vaccine
Single-cell analysis reveals divergent responses of human dendritic cells to the MVA vaccine
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DOI：
10.1126/scisignal.abd9720
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发表时间：
2021-08-24
影响因子：
7.3
通讯作者：
Manel, Nicolas
中科院分区：
文献类型：
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作者：
Doring, Marius;De Azevedo, Kevin;Manel, Nicolas
改良安卡拉牛痘（MVA）是一种减毒活人类天花疫苗，也是开发抗传染病和癌症新疫苗的载体。MVA对免疫系统的有效激活部分依赖于其与树突状细胞（DC）的接触。树突状细胞的MVA感染导致多种结果，包括细胞因子的产生，T细胞刺激的共刺激分子的激活和细胞死亡。在这里，我们研究了这些不同的反应是如何在人类DC中协调的。单细胞分析显示，在DC中MVA感染的反应仅限于早期病毒基因表达。为了应对病毒周期的早期事件，我们发现DC分为三个不同的簇。感染细胞簇通过cGAS、STING、TBK1和IRF3介导的细胞内先天免疫途径感知MVA基因组，随后产生炎性细胞因子。作为对这些细胞因子的反应，一群未感染的旁观者细胞增加了共刺激分子的表达。一个单独的集群感染细胞进行半胱天冬酶依赖性凋亡。诱导细胞凋亡持续抑制后的先天免疫途径介质独立于先前描述的IRF依赖性或复制依赖性途径，是对早期MVA基因表达的反应。总之，我们的研究确定了MVA与人DC相互作用的多种机制。
Modified vaccinia Ankara (MVA) is a live, attenuated human smallpox vaccine and a vector for the development of new vaccines against infectious diseases and cancer. Efficient activation of the immune system by MVA partially relies on its encounter with dendritic cells (DCs). MVA infection of DCs leads to multiple outcomes, including cytokine production, activation of costimulatory molecules for T cell stimulation, and cell death. Here, we examined how these diverse responses are orchestrated in human DCs. Single-cell analyses revealed that the response to MVA infection in DCs was limited to early viral gene expression. In response to the early events in the viral cycle, we found that DCs grouped into three distinct clusters. A cluster of infected cells sensed the MVA genome by the intracellular innate immunity pathway mediated by cGAS, STING, TBK1, and IRF3 and subsequently produced inflammatory cytokines. In response to these cytokines, a cluster of noninfected bystander cells increased costimulatory molecule expression. A separate cluster of infected cells underwent caspase-dependent apoptosis. Induction of apoptosis persisted after inhibition of innate immunity pathway mediators independently of previously described IRF- -dependent or replication-dependent pathways and was a response to early MVA gene expression. Together, our study identified multiple mechanisms that underlie the interactions of MVA with human DCs.