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

Konstantin Lutz; Andrea Musumeci; Christopher Sie; Ezgi Dursun; Elena Winheim; Johannes Bagnoli; Christoph Ziegenhain; Lisa Rausch; Volker Bergen; Malte D Luecken; Robert A J Oostendorp; Barbara U Schraml; Fabian J Theis; Wolfgang Enard; Thomas Korn; Anne B Krug

doi:10.1038/s41467-022-31054-4

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

Nat Commun. 2022 Jun 16;13(1):3456. doi: 10.1038/s41467-022-31054-4.

Authors

Konstantin Lutz^#¹, Andrea Musumeci^#¹, Christopher Sie², Ezgi Dursun¹, Elena Winheim¹, Johannes Bagnoli³, Christoph Ziegenhain^{3

4}, Lisa Rausch¹, Volker Bergen^{5

6}, Malte D Luecken⁵, Robert A J Oostendorp⁷, Barbara U Schraml^{8

9}, Fabian J Theis^{5

6}, Wolfgang Enard³, Thomas Korn^{2

10

11}, Anne B Krug¹²

Affiliations

¹ Institute for Immunology, Biomedical Center, LMU Munich, Großhaderner Str. 9, 82152, Planegg-Martinsried, Germany.
² Institute for Experimental Neuroimmunology, Technical University of Munich, School of Medicine, Ismaninger Str. 22, 81675, Munich, Germany.
³ Anthropology and Human Genomics, Faculty of Biology, LMU Munich, Großhaderner Str. 2, 82152, Planegg-Martinsried, Germany.
⁴ Department of Cell and Molecular Biology, Karolinska Institute, Stockholm, Sweden.
⁵ Institute of Computational Biology, Helmholtz Center Munich, Ingolstädter Landstr. 1, 85764, Neuherberg, Germany.
⁶ Department of Mathematics, Technical University of Munich, Boltzmannstraße 3, 85748, Garching, Germany.
⁷ Technical University of Munich, School of Medicine, Department of Internal Medicine III, Ismaninger Str. 22, 81675, Munich, Germany.
⁸ Institute for Cardiovascular Physiology and Pathophysiology, Biomedical Center, LMU Munich, Großhaderner Str. 9, 82152, Planegg-Martinsried, Germany.
⁹ Walter-Brendel-Centre of Experimental Medicine, University Hospital, LMU Munich, 82152, Planegg-Martinsried, Germany.
¹⁰ Department of Neurology, Technical University of Munich School of Medicine, Ismaninger Str. 22, 81675, Munich, Germany.
¹¹ Munich Cluster for Systems Neurology (SyNergy), Feodor-Lynen-Str. 17, 81377, Munich, Germany.
¹² Institute for Immunology, Biomedical Center, LMU Munich, Großhaderner Str. 9, 82152, Planegg-Martinsried, Germany. anne.krug@med.uni-muenchen.de.

^# Contributed equally.

Abstract

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^-/loSiglec-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^-/loSiglec-H⁺CCR9^lo DC precursor pool cells expressing high levels of Ly6D and lacking expression of transcription factor Zbtb46 contain CCR9^loB220^hi immediate pDC precursors and CCR9^loB220^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^hiZbtb46^- 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.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Animals
Antigens, Ly* / genetics
Antigens, Ly* / metabolism
CD11c Antigen / metabolism
Cell Differentiation / genetics
Dendritic Cells* / metabolism
GPI-Linked Proteins / metabolism
Mice
Sialic Acid Binding Immunoglobulin-like Lectins* / genetics
Sialic Acid Binding Immunoglobulin-like Lectins* / metabolism
Stem Cells / metabolism
Transcription Factors

Substances

Antigens, Ly
CD11c Antigen
GPI-Linked Proteins
Ly6d protein, mouse
Sialic Acid Binding Immunoglobulin-like Lectins
Transcription Factors
Zbtb46 protein, mouse