Abstract Plasmacytoid dendritic cells (pDCs) are major producers of type I/III interferons. As these cytokines are crucial for antiviral defense, it is assumed to be also the case for pDCs. However, robust evidence supporting this dogma is scarce. Genetic mutations or pharmacological manipulations causing pDC loss or disrupting their interferon production affect other immune cells, which could confound interpretation. To overcome this bottleneck, we engineered pDC-less mice, specifically and constitutively devoid of pDCs as expressing diphtheria toxin under coordinated control of the Siglech and Pacsin1 genes co-expressed uniquely in pDCs. pDC-less mice mounted protective intrinsic and innate immune responses against systemic infection with mouse Cytomegalovirus, and were more resistant to intranasal infection with influenza virus and SARS-CoV2. Thus, contrary to dogma, pDCs and their interferon production proved dispensable or deleterious during systemic or respiratory viral infections, respectively. pDC-less mice will enable rigorously revisiting the roles of pDCs in health and disease.

Plasmacytoid dendritic cells are dispensable or detrimental in murine systemic or respiratory viral infections