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Tissue-specific differentiation of a circulating CCR9- pDC-like common dendritic cell precursor

ABSTRACT: Committed precursors of conventional dendritic cells (pre-cDCs) derived from the common DC progenitor which differentiate into cDC subpopulations in peripheral tissues have been identified, but committed precursors for plasmacytoid DCs (pDCs) have not been found. Here we show that CDP-derived ‘CCR9- MHCIIlow BST2+ Siglec-H+ pDCs from murine bone marrow which enter the circulation and peripheral tissues have a common DC precursor function in vivo in the steady state. Upon adoptive transfer the fate of CCR9- pDC-like precursors is governed by the tissues they enter. In the bone marrow and liver most transferred CCR9- pDC-like precursors differentiate into CCR9+ pDCs, whereas in peripheral lymphoid organs, lung and intestine they can give rise to CCR9+ pDCs and cDCs. Thus, CCR9- pDC-like cells are novel CDP-derived circulating DC precursors with pDC and cDC potential, whose final differentiation depends on tissue-specific factors allowing adaptation to local requirements.

ORGANISM(S): Mus musculus

PROVIDER: GSE37996 | GEO | 2012/05/16

SECONDARY ACCESSION(S): PRJNA167031

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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Tissue-specific differentiation of a circulating CCR9- pDC-like common dendritic cell precursor

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