Summary

The formation of mammalian dendritic cells (DCs) is controlled by multiple hematopoietic transcription factors, including IRF8. Loss of IRF8 exerts a differential effect on DC subsets, including plasmacytoid DCs (pDCs) and the classical DC lineages cDC1 and cDC2. In humans, cDC2-related subsets have been described including AXL+SIGLEC6+ pre-DC, DC2 and DC3. The origin of this heterogeneity is unknown. Using high-dimensional analysis, in vitro differentiation, and an allelic series of human IRF8 deficiency, we demonstrated that cDC2 (CD1c+DC) heterogeneity originates from two distinct pathways of development. The lymphoid-primed IRF8hi pathway, marked by CD123 and BTLA, carried pDC, cDC1, and DC2 trajectories, while the common myeloid IRF8lo pathway, expressing SIRPA, formed DC3s and monocytes. We traced distinct trajectories through the granulocyte-macrophage progenitor (GMP) compartment showing that AXL+SIGLEC6+ pre-DCs mapped exclusively to the DC2 pathway. In keeping with their lower requirement for IRF8, DC3s expand to replace DC2s in human partial IRF8 deficiency.

Overall design

overall_design too long too uplode

Contributors

Urszula Cytlak 1, Anastasia Resteu 1, Sarah Pagan 1, Kile Green 1, Paul Milne 1, Sheetal Maisuria 2, David McDonald 3, Gillian Hulme 3, Andrew Filby 3, Benjamin Carpenter 4, Rachel Queen 3, Sophie Hambleton 5, Rosie Hague 6, Hana Lango Allen 7, James E D Thaventhiran 8, Gina Doody 9, Matthew Collin 10, Venetia Bigley 11

Contact

venetia.bigley@ncl.ac.uk.(Venetia Bigley)