Dual Role of Plasmacytoid Dendritic Cells in Humoral and CD8⁺ T Cell Memory Post COVID-19 mRNA Vaccination

Pizzichetti, C.; Latino, I.; Virgilio, T.; Capucetti, A.; Chahine, K.; Cascione, L.; Moro, S. G.; Brugger, M.; Kozarac, N.; Pulfer, A.; Renner, L.; Thakur, R. S.; Benarafa, C.; Legler, D. F.; Gonzalez, S. F.

doi:10.1101/2025.06.13.659539

bioRxiv · 10.1101/2025.06.13.659539

Dual Role of Plasmacytoid Dendritic Cells in Humoral and CD8⁺ T Cell Memory Post COVID-19 mRNA Vaccination

Pizzichetti, C.·Latino, I.·Virgilio, T.·Capucetti, A.·Chahine, K.·Cascione, L.·Moro, S. G.·Brugger, M.·Kozarac, N.·Pulfer, A.·Renner, L.·Thakur, R. S.·Benarafa, C.·Legler, D. F.·Gonzalez, S. F.

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Abstract

The Pfizer-BioNTech coronavirus vaccine (BNT162b2), one of the first nanoparticle-based vaccines approved by the World Health Organisation (WHO), demonstrated 95% efficacy in preventing against Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection. However, the precise mechanism of action underlying its effectiveness remains poorly understood. This study investigated the early immune responses in the draining lymph node (dLN) and its role in mediating antiviral protection following vaccination. Here, we focused on the involvement of antigen-presenting cells (APCs) in adaptive immunity. In this study, we demonstrated that the Pfizer-BioNTech coronavirus vaccine is rapidly transported to the dLN and is primarily captured by leukocytes that initiate the expression of the viral antigenic spike protein. Notably, we demonstrated that plasmacytoid dendritic cells (pDCs) are key orchestrators of the inflammatory and humoral response, as their specific depletion led to impaired antibody production and diminished neutralization capacity. Furthermore, single-cell transcriptomic analysis revealed an interaction between pDCs and CD8+ T cells that facilitates T cell activation. In vivo experiments confirmed that pDCs expressing the viral spike protein directly engage with CD8+ T cells, promoting their differentiation and expansion. Moreover, the absence of pDCs affected the formation of antigen-specific memory T cells. Overall, these findings highlight that pDCs are essential players in mediating both adaptive and humoral responses to the Pfizer-BioNTech coronavirus vaccine, providing insights into the mechanistic functioning of mRNA vaccines and establishing a novel role for pDCs as professional APCs.

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Pizzichetti, C., Latino, I., Virgilio, T., Capucetti, A., Chahine, K., Cascione, L., Moro, S. G., Brugger, M., Kozarac, N., Pulfer, A., Renner, L., Thakur, R. S., Benarafa, C., Legler, D. F., Gonzalez, S. F.. 2025-06-16. Dual Role of Plasmacytoid Dendritic Cells in Humoral and CD8⁺ T Cell Memory Post COVID-19 mRNA Vaccination. https://doi.org/10.1101/2025.06.13.659539

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