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Differential IRF8 Transcription Factor Requirement Defines Two Pathways of Dendritic Cell Development in Humans

Lookup NU author(s): Dr Urszula Cytlak-Chaudhuri, Dr Anastasia Resteu, Sarah Pagan, Dr Kile Green, Dr Paul Milne, Dr Gill Hulme, Dr Andrew Filby, Dr Rachel Queen, Professor Sophie Hambleton, Professor Matthew Collin, Dr Venetia Bigley

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This work is licensed under a Creative Commons Attribution 4.0 International License (CC BY 4.0).


Abstract

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.


Publication metadata

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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