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

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 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 IRF8^hi pathway, marked by CD123 and BTLA, carried pDC, cDC1, and DC2 trajectories, while the common myeloid IRF8^lo 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.

SUBMITTER: Cytlak U

PROVIDER: S-EPMC7447982 | biostudies-literature |

REPOSITORIES: biostudies-literature

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