Ly6D+Siglec-H+ precursors contribute to conventional dendritic cells via a Zbtb46+Ly6D+ intermediary stage

Plasmacytoid and conventional dendritic cells (pDC and cDC) are generated from progenitor cells in the bone marrow and commitment to pDCs or cDC subtypes may occur in earlier and later progenitor stages. Cells within the CD11c(+)MHCII(-/lo)Siglec-H(+)CCR9(lo) DC precursor fraction of the mouse bone marrow generate both pDCs and cDCs. Here we investigate the heterogeneity and commitment of subsets in this compartment by single-cell transcriptomics and high-dimensional flow cytometry combined with cell fate analysis: Within the CD11c(+)MHCII(-/lo)Siglec-H(+)CCR9(lo) DC precursor pool cells expressing high levels of Ly6D and lacking expression of transcription factor Zbtb46 contain CCR9(lo)B220(hi) immediate pDC precursors and CCR9(lo)B220(lo) (lo-lo) cells which still generate pDCs and cDCs in vitro and in vivo under steady state conditions. cDC-primed cells within the Ly6D(hi)Zbtb46(-) lo-lo precursors rapidly upregulate Zbtb46 and pass through a Zbtb46(+)Ly6D(+) intermediate stage before acquiring cDC phenotype after cell division. Type I IFN stimulation limits cDC and promotes pDC output from this precursor fraction by arresting cDC-primed cells in the Zbtb46(+)Ly6D(+) stage preventing their expansion and differentiation into cDCs. Modulation of pDC versus cDC output from precursors by external factors may allow for adaptation of DC subset composition at later differentiation stages. The ontogeny of conventional and plasmacytoid dendritic cells (DC) and how these two cell types are related is not fully known. Here the authors identify a pool of bone marrow precursor cells expressing Ly6D Siglec-H and Zbtb46 that can differentiate into either cDC or pDC and show that type I IFN can limit cDC and favor pDC output from these precursors.

Automated summary

This study investigates the heterogeneity and commitment of precursor cells in the mouse bone marrow that can differentiate into plasmacytoid and conventional dendritic cells (pDC and cDC). The authors identify a specific population of precursor cells expressing certain markers that can give rise to both pDCs and cDCs. They also show that type I interferon can regulate the balance between pDC and cDC production from these precursor cells. These findings shed light on the ontogeny and differentiation of dendritic cells.