The formation of human dendritic cells (DC) is controlled by multiple hematopoietic transcription factors, including IRF8. Loss of IRF8 differentially affects plasmacytoid DC (pDC) and the classical DC lineages, cDC1 and cDC2. Additionally, cDC2 are heterogeneous, comprising DC-like DC2 and monocyte-like DC3. Using high dimensional analysis, in vitro differentiation, and an allelic series of human IRF8 deficiency, we show that CD1c+DC heterogeneity originates from two distinct pathways of DC development. The lymphoid-primed IRF8high pathway carries pDC, cDC1, and DC2 trajectories, while the common myeloid IRF8low pathway forms DC3 and monocytes. We trace distinct trajectories of cDC1, DC2 and DC3 through the GMP showing that AXL+SIGLEC6+ pre-DC map exclusively to the DC2 pathway. The preservation of human CD1c+DC in partial IRF8 deficiency is explained by the replacement of DC2 by an expanded DC3 population. These observations are congruent with lineage-primed models of hematopoiesis, illustrating new links between immune cell function and ontogeny.
Cytlak, Urszula and Resteu, Anastasia and Pagan, Sarah and Green, Kile and Milne, Paul and Maisuria, Sheetal and McDonald, David and Hulme, Gillian and Filby, Andrew and Carpenter, Benjamin and Queen, Rachel and Hambleton, Sophie and Hague, Rosie and Allen, Hana Lango and Thaventhiran, James and Doody, Gina and Collin, Matthew and Bigley, Venetia, Differential IRF8 Requirement Defines Two Pathways of Dendritic Cell Development in Humans (April 3, 2019). Available at SSRN: https://ssrn.com/abstract=3365028 or http://dx.doi.org/10.2139/ssrn.3365028
This version of the paper has not been formally peer reviewed.
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