Differential response of human plasmacytoid pre-dendritic cells to SARS-CoV-2 variants

SARS-CoV-2 variants have been involved in various waves of the COVID19 pandemic and showed different pathogenicity and inflammatory potential. Whether they can induce different patterns of innate immune activation in antigen-presenting cells is poorly understood. Here, we investigated the ability of primary plasmacytoid pre-dendritic cells (pDC), type 2 dendritic cells (DC2), and monocytes isolated from healthy blood donors to respond to SARS-CoV-2 variants. Transcriptomic profiling using RNA sequencing revealed that pDC respond differentially to SARS-CoV-2 variants, while DC2 and monocytes do not. Functional studies showed that pDC undergo differential activation programs upon SARS-CoV-2 variant stimulation. The Alpha B220/95 and Delta variants induced P1-/P2-pDC effector phenotypes, characterized by strong IFN-α production. On the contrary, BA.1 variant turned pDC into a predominant T cell activating P3 phenotype, with less IFN-α and IFN-λ production, and stronger proinflammatory and CD4+T cell responses. Our results indicate that pDC activation and diversification pattern can be differentially controlled by SARS-CoV-2 variants, which may influence disease severity