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

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) variants have been involved in various waves of the COVID-19 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 donors to respond to SARS-CoV-2 variants. Transcriptomic profiling using RNA sequencing revealed that pDC respond differentially to SARS-CoV-2 variants, unlike DC2 and monocytes. Functional studies showed that pDC undergo differential activation programs upon SARS-CoV-2 variant stimulation. The Alpha and Delta variants induced P1-/P2-pDC effector phenotypes, characterized by strong IFN-α production. In contrast, the Omicron variant predominantly triggered a T cell-activating P3 phenotype, with lower IFN-α and IFN-λ production, and stronger proinflammatory and CD4⁺T cell responses. Our results indicate that SARS-CoV-2 variants can control pDC diversification pattern in different ways, which may influence disease severity.