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 toward cDC development during in vivo viral infection. Subsequent characterization of the transcriptional and epigenetic landscape of fms-like tyrosine kinase 3+ (Flt3+) DC progenitors and follow-up studies revealed increased apoptosis and reduced proliferation in different individual DC-progenitors as well as a profound type I interferon (IFN-I)-dependent ablation of pre-pDCs, but not pre-DC precursors, after both acute and chronic LCMV infections. In addition, integrated genomic analysis identified altered activity of 34 transcription factors in Flt3+ DC progenitors from infected mice, including two regulators of Glucocorticoid (GC) responses. Subsequent studies demonstrated that addition of GCs to DC progenitors led to downregulated pDC-primed-genes while upregulating cDC-primed-genes, and that endogenous GCs selectively decreased pDC, but not cDC, numbers upon in vivo LCMV infection. These findings demonstrate a significant ablation of pre-pDCs in infected mice and identify GCs as suppressors of pDC generation from early progenitors. This provides a potential explanation for the impaired pDC development following viral infection and links pDC numbers to the hypothalamic-pituitary-adrenal axis.
Keywords: dendritic cell development; glucocorticoids; interferon; plasmacytoid dendritic cells; viral infection.