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IRF-8 extinguishes neutrophil production and promotes dendritic cell lineage commitment in both myeloid and lymphoid progenitors (Illumina).

ABSTRACT: While most blood lineages are assumed to mature through a single cellular and developmental route downstream of hematopoietic stem cells (HSCs), dendritic cells (DCs) can be derived from both myeloid and lymphoid progenitors in vivo. To determine how distinct progenitors can generate similar downstream lineages, we examined the transcriptional changes that accompany loss of in vivo myeloid potential as common myeloid progenitors (CMPs) differentiate into common dendritic cell progenitors (CDPs), and as lymphoid-primed multipotent progenitors (LMPPs) differentiate into all lymphoid progenitors (ALPs). Microarray studies revealed that Interferon regulatory factor 8 (IRF-8) expression increased during each of these transitions. Competitive reconstitutions using Irf8-/- bone marrow demonstrated cell-intrinsic defects in the formation of CDPs and all splenic dendritic cell subsets. Irf8-/- CMPs and, unexpectedly, Irf8-/- ALPs produced more neutrophils in vivo than their wild type counterparts at the expense of DCs. Retroviral expression of IRF-8 in multiple progenitors led to reduced neutrophil production and increased numbers of DCs, even in the granulocyte-macrophage progenitor (GMP), which does not normally possess conventional DC potential. These data suggest that IRF-8 represses a neutrophil module of development and promotes convergent DC development from multiple lymphoid and myeloid progenitors autonomously of cellular context.

ORGANISM(S): Mus musculus

PROVIDER: GSE34915 | GEO | 2012/01/07

SECONDARY ACCESSION(S): PRJNA156249

REPOSITORIES: GEO

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Project description:Dendritic cells (DCs) in lymphoid tissue comprise conventional DCs (cDCs) and plasmacytoid DCs (pDCs) that develop from common DC progenitors (CDPs). CDPs are Flt3+c-kitintM-CSFR+ and reside in bone marrow. Here we describe a two-step culture system that recapitulates DC development from c-kithiFlt3-/lo multipotent progenitors (MPPs) into CDPs and further into cDC and pDC subsets. MPPs and CDPs are amplified in vitro with Flt3 ligand, stem cell factor, hyper-IL-6 and insulin- like growth factor-1. The four-factor cocktail readily induces self-renewal of MPPs and their progression into CDPs and has no self-renewal activity on CDPs. The amplified CDPs respond to all known DC poietins and generate all lymphoid tissue DCs in vivo and in vitro. Additionally, in vitro CDPs recapitulate the cell surface marker and gene expression profile of in vivo CDPs and possess a DC-primed transcription profile. Transforming growth factor-Î²1 (TGF-Î²1) impacts on CDPs and directs their differentiation towards cDCs. Genome-wide gene expression profiling of TGF-Î²1-induced genes identified transcription factors, such as interferon regulatory factor-4 (IRF-4) and RelB, that are implicated as instructive factors for cDC subset specification. TGF-Î²1 also induced the transcription factor inhibitor of differentiation/DNA binding 2 (Id2) that suppresses pDC development. Thus, TGF-Î²1 directs CDP differentiation into cDC by inducing both cDC instructive factors and pDC inhibitory factors. 20 samples in total. Multipotent progenitor - MPP_1 - MPP_2 Common dendritic cell progenitor - CDP_1 - CDP_2 Plasmacytoid dendritic cell - pDC_1 - pDC_2 Conventional dendritic cell - cDC_1 - cDC_2 In vivo common dendritic cell progenitor - In vivo CDP_1 - In vivo CDP_2 Untreated common dendritic cell progenitor (CDP) - CDP_0h_1 - CDP_0h_2 TGF-beta1 treated (4 hours) CDP - CDP_4h_1 - CDP_4h_2 TGF-beta1 treated (8 hours) CDP - CDP_8h_1 - CDP_8h_2 TGF-beta1 treated (12 hours) CDP - CDP_12h_1 - CDP_12h_2 TGF-beta1 treated (24 hours) CDP - CDP_24h_1 - CDP_24h_2

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IRF-8 extinguishes neutrophil production and promotes dendritic cell lineage commitment in both myeloid and lymphoid progenitors (Illumina).

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