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


Type
Article
Change log
Authors
Cytlak, Urszula 
Resteu, Anastasia 
Pagan, Sarah 
Green, Kile 
Milne, Paul 
Abstract

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 highdimensional 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 lymphoidprimed 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.

Description
Keywords
CyTOF, IRF8, dendritic cell, hematopoiesis, immunity, primary immunodeficiency, single-cell RNA sequencing, transcription factor, Animals, Antigens, CD1, Antigens, CD34, Cell Line, Cell Lineage, Dendritic Cells, Glycoproteins, Hematopoiesis, Hematopoietic Stem Cells, Humans, Interferon Regulatory Factors, Interleukin-3 Receptor alpha Subunit, Lipopolysaccharide Receptors, Mice, Receptors, Immunologic
Journal Title
Immunity
Conference Name
Journal ISSN
1074-7613
1097-4180
Volume Title
53
Publisher
Elsevier
Sponsorship
Cambridge University Hospitals NHS Foundation Trust (CUH) (BRC 2012-2017)