pDC-like cells are pre-DC2 and require Klf4 to control homeostatic CD4 T cells

Plasmacytoid dendritic cells (pDCs) have been shown to play an important role during immune responses, ranging from initial viral control through the production of type I interferons (IFNs) to antigen presentation. However, recent evidence uncovered unexpected heterogeneity among pDCs. Notably we identified a new subset, referred to as pDC-like cells, that resembles pDCs but shares cDC features. Here we show that this subset is a circulating progenitor distinct from common DC progenitors (CDP), with prominent cDC2 precursor potential. This precursor subset responds to homeostatic cytokines, such as macrophage colony stimulating factor (M-CSF) by expanding and differentiating into cDC2 that efficiently prime Th17 cell. Development of pDC-like cells into CX3CR1+ESAM- cDC2b but not CX3CR1- ESAM+ cDC2a requires the transcription factor KLF4. Finally, we show that under homeostatic conditions this developmental pathway regulates the immune threshold at barrier sites, by controlling the pool of Th17 cells within the skin draining lymph nodes. Overall design: Bulk RNA Sequencing of sort-purified DC subsets derived from different tissues.