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

• Published in: Nature communications Vol. 13; no. 1; p. 3456
• Main Authors: Lutz, Konstantin, Musumeci, Andrea, Sie, Christopher, Dursun, Ezgi, Winheim, Elena, Bagnoli, Johannes, Ziegenhain, Christoph, Rausch, Lisa, Bergen, Volker, Luecken, Malte D, Oostendorp, Robert A J, Schraml, Barbara U, Theis, Fabian J, Enard, Wolfgang, Korn, Thomas, Krug, Anne B
• Format: Journal Article
• Language: English
• Published: England Nature Publishing Group 16.06.2022; Nature Publishing Group UK; Nature Portfolio
• Subjects: Bone marrow; CD11c antigen; Cell division; Cell fate; Cells (biology); Dendritic cells; Dendritic structure; Differentiation; Flow cytometry; Heterogeneity; Hydrogen; Interferon; Medicin och hälsovetenskap; Ontogeny; Osteoprogenitor cells; Phenotypes; Precursors; Progenitor cells; Transcriptomics
• ISSN: 2041-1723; 2041-1723
• DOI: 10.1038/s41467-022-31054-4

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 Siglec-H CCR9 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 Siglec-H CCR9 DC precursor pool cells expressing high levels of Ly6D and lacking expression of transcription factor Zbtb46 contain CCR9 B220 immediate pDC precursors and CCR9 B220 (lo-lo) cells which still generate pDCs and cDCs in vitro and in vivo under steady state conditions. cDC-primed cells within the Ly6D 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.