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Division of labor for vaccine responses: The modified vaccinia virus Ankara (MVA) is an attenuated pox virus vaccine and may be a safe vector for vaccines against other viruses. Dendritic cells (DCs) are among the first responders to invading pathogens and are thus critical to vaccine efficacy. Doring et al. used single-cell RNA sequencing to analyze the response of human DCs to MVA. They found a division of labor among DCs in which infected DCs produced inflammatory cytokines that activated nearby, noninfected DCs that, in turn, expressed T cell costimulatory molecules. The subsequent and rapid death of infected DCs occurred in a parallel but independent manner from that of the cytokine response. The resulting insight into the pathways involved may inform the development of additional MVA-based vaccines. 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. [ABSTRACT FROM AUTHOR]