Tissue & cell · 2026
Establishment of a dendritic cell differentiation system faithfully recapitulating multiple DC subsets in autoimmune disease.
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Bi Siqi, Tian Ye, Le Yiping, Li Honglin, Wang You, Liu Can, Zhou Haibo
Аннотация
OBJECTIVE: Human dendritic cell (DC) subsets are pivotal in autoimmune disease, but their extreme rarity in patient tissues limits study. We aimed to build a physiologically relevant in vitro platform that reconstructs all major human DC subpopulations in an IFN-rich autoimmune-like microenvironment and to define how IFN signaling shapes DC lineage commitment and functional specialization.
METHODS: CD34⁺ hematopoietic progenitor cells from umbilical cord blood were differentiated in a feeder-free culture with type I and type II IFNs. DC phenotypes were profiled by multicolor flow cytometry; functions were tested by innate stimulation and T cell-activation cocultures. Single-cell RNA-seq (3 timepoints during differentiation) with trajectory inference reconstructed differentiation hierarchies, and in vitro transcriptional profiles were compared with lupus patient scRNA-seq datasets.
RESULTS: The IFN-enriched system generated cDC1s, cDC2s, pDCs, ASDCs, mregDCs, and DC3-like populations, each showing lineage-specific surface markers, canonical innate immune sensing programs, and distinct T cell-stimulatory capacities. scRNA-seq demonstrated high similarity to disease-associated DC populations in autoimmune samples. Trajectory analyses mapped progenitor-to-mature DC progression and revealed a pDC bifurcation toward canonical pDCs or ASDC-like states. Notably, IFN exposure selectively promoted inflammatory DC programs marked by elevated interferon-stimulated genes (ISGs) and functional polarization toward ASDC-related phenotypes.
CONCLUSION: IFN signaling is a key determinant of DC diversification and functional specialization, and this platform enables genetic screening and mechanistic interrogation of human DC biology in autoimmune pathogenesis.
METHODS: CD34⁺ hematopoietic progenitor cells from umbilical cord blood were differentiated in a feeder-free culture with type I and type II IFNs. DC phenotypes were profiled by multicolor flow cytometry; functions were tested by innate stimulation and T cell-activation cocultures. Single-cell RNA-seq (3 timepoints during differentiation) with trajectory inference reconstructed differentiation hierarchies, and in vitro transcriptional profiles were compared with lupus patient scRNA-seq datasets.
RESULTS: The IFN-enriched system generated cDC1s, cDC2s, pDCs, ASDCs, mregDCs, and DC3-like populations, each showing lineage-specific surface markers, canonical innate immune sensing programs, and distinct T cell-stimulatory capacities. scRNA-seq demonstrated high similarity to disease-associated DC populations in autoimmune samples. Trajectory analyses mapped progenitor-to-mature DC progression and revealed a pDC bifurcation toward canonical pDCs or ASDC-like states. Notably, IFN exposure selectively promoted inflammatory DC programs marked by elevated interferon-stimulated genes (ISGs) and functional polarization toward ASDC-related phenotypes.
CONCLUSION: IFN signaling is a key determinant of DC diversification and functional specialization, and this platform enables genetic screening and mechanistic interrogation of human DC biology in autoimmune pathogenesis.