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Lookup NU author(s): Dr Urszula Cytlak-ChaudhuriORCiD, Dr Anastasia ResteuORCiD, Sarah Pagan, Dr Kile GreenORCiD, Dr Paul Milne, Dr Gill HulmeORCiD, Professor Andrew FilbyORCiD, Dr Rachel Queen, Professor Sophie Hambleton, Professor Matthew CollinORCiD, Dr Venetia BigleyORCiD
This work is licensed under a Creative Commons Attribution 4.0 International License (CC BY 4.0).
The formation of mammalian dendritic cells (DC) is controlled by multiple hematopoietic transcription factors, including IRF8. Loss of IRF8 exerts a differential effect on DC subsets; plasmacytoid DC (pDC) 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 DC3 and monocytes. We traced distinct trajectories through the Granulocyte-Macrophage Progenitor (GMP) compartment showing that AXL+SIGLEC6+ pre-DC mapped exclusively to the DC2 pathway. In keeping with their lower requirement for IRF8, DC3 expand to replace DC2 in human partial IRF8 deficiency.
Author(s): Cytlak U, Resteu A, Pagan S, Green K, Milne P, Maisuria S, McDonald D, Hulme G, Filby A, Carpenter B, Queen R, Hambleton S, Hague R, Lango Allen H, Thaventhiran JED, Doody G, Collin M, Bigley V
Publication type: Article
Publication status: Published
Journal: Immunity
Year: 2020
Volume: 53
Issue: 2
Pages: 353-370
Print publication date: 18/08/2020
Online publication date: 30/07/2020
Acceptance date: 02/07/2020
Date deposited: 11/08/2020
ISSN (print): 1074-7613
ISSN (electronic): 1097-4180
Publisher: Cell Press
URL: https://doi.org/10.1016/j.immuni.2020.07.003
DOI: 10.1016/j.immuni.2020.07.003
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