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

Immunity. 2020 Aug 18;53(2):353-370.e8. doi: 10.1016/j.immuni.2020.07.003. Epub 2020 Jul 30.


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.

Keywords: CyTOF; IRF8; dendritic cell; hematopoiesis; immunity; primary immunodeficiency; single-cell RNA sequencing; transcription factor.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Antigens, CD1 / metabolism
  • Antigens, CD34 / metabolism*
  • Cell Line
  • Cell Lineage / immunology
  • Dendritic Cells / cytology*
  • Dendritic Cells / immunology
  • Glycoproteins / metabolism
  • Hematopoiesis / physiology*
  • Hematopoietic Stem Cells / cytology
  • Humans
  • Interferon Regulatory Factors / metabolism*
  • Interleukin-3 Receptor alpha Subunit / metabolism
  • Lipopolysaccharide Receptors / metabolism
  • Mice
  • Receptors, Immunologic / metabolism


  • Antigens, CD1
  • Antigens, CD34
  • BTLA protein, human
  • CD14 protein, human
  • CD1C protein, human
  • Glycoproteins
  • IL3RA protein, human
  • Interferon Regulatory Factors
  • Interleukin-3 Receptor alpha Subunit
  • Lipopolysaccharide Receptors
  • Receptors, Immunologic
  • interferon regulatory factor-8