Plasmacytoid Dendritic Cell Lineage Adaptations During a Viral Infection

Plasmacytoid dendritic cells (pDCs) are best known for their outstanding ability to rapidly produce large amounts of type I interferons (IFN-I), which are key antiviral mediators. However, after their initial IFN-I burst, the pDC lineage undergoes a number of adaptations that converge on the attenuation of pDC-derived interferons, ensuring their production remains short-lived regardless of whether the pathogen is cleared or persists. The convergence of multiple host adaptations that result in reduced pDC numbers and/or function after infection highlights the double-edged sword nature of pDCs: while they can be beneficial for antiviral defense, they can also drive tissue pathology. In this review, we summarize selected pDC-lineage adaptations that arise after their initial IFN-I peak following a viral infection, including compromised pDC development from bone marrow progenitors, fate plasticity that enables pDC conversion into conventional dendritic cells type 2 (cDC2)-like cells, and loss of the pDCs' hallmark capacity to produce IFN-I. We also provide an overview of the underlying molecular mechanisms contributing to the aforementioned adaptations, discuss potential evolutionary advantages, and highlight future avenues to dissect the fundamental biology of pDC reprogramming with the ultimate goal of leveraging these insights to therapeutically target pDCs in infections and beyond.