Dendritic Cell Type 3 Arises from Ly6C+ Monocyte-Dendritic Cell Progenitors

Conventional dendritic cells (cDCs) are professional antigen-presenting cells that control the adaptive immune response. Their subsets and developmental origins have been intensively investigated; however, they are still not fully understood because their phenotypes, especially in the cDC2 lineage and the recently described DC3 cells, overlap with monocytes. Here, using the LEGENDScreen to profile DC vs. monocyte lineages, we found sustained expression of Flt3 and CD45RB through the whole DC lineage, allowing DCs and their precursors to be distinguished from monocytes. Using fate mapping models, RNA-seq and adoptive transfer, we show that Flt3+CD11c- "R2" cells, previously proposed to be monocytes, are instead DC progenitors (pro-DCs) that derived directly from Ly6C+ monocyte-DC progenitors (MDPs) and predominantly give rise to DC3 cells. These findings clarify DC ontogeny and reveal DC3 as a unique DC lineage phenotypically related to but developmentally different from monocytes.