Genomic Analysis of Progenitors in Viral Infection Implicates Glucocorticoids as Suppressors of Plasmacytoid Dendritic Cell Generation.

Plasmacytoid Dendritic cells (pDCs) are the most potent producers of interferons, which are critical antiviral cytokines. pDC development is, however, compromised following a viral infection, and this phenomenon, as well as its relationship to conventional (c)DC development is still incompletely understood. By using lymphocytic choriomeningitis virus (LCMV) infection in mice as a model system, we observed that DC progenitors skewed away from pDC and towards cDC development during Significance Statement: Plasmacytoid dendritic cells (pDCs) play critical roles in antiviral responses. However, adaptations of DC progenitors lead to compromised pDC generation after viral infection. Here, we characterized the transcriptional and epigenetic landscapes of DC progenitors after infection. We observed widespread changes in gene expression and chromatin accessibility, reflecting shifts in proliferation, apoptosis, and differentiation potential into various DC subsets. Notably, we identified alterations in the predicted activity of 34 transcription factors, including two regulators of glucocorticoid responses. Our data demonstrate that glucocorticoids inhibit pDC generation by reprogramming DC progenitors. These findings establish a molecular framework for understanding how DC progenitors adapt to infection and highlight the role of glucocorticoid signaling in this process.