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Notch signaling facilitates in vitro generation of cross-presenting classical dendritic cells

ABSTRACT: The IRF8-dependent subset of classical dendritic cells (cDC), termed cDC1, is important for cross-priming cytotoxic T cell responses against pathogens and tumors. Culture of hematopoietic progenitors with DC growth factor Flt3 ligand (Flt3L) yields very few cDC1 (in humans) or only immature "cDC1-like" cells (in the mouse). We report that OP9 stromal cells expressing Notch ligand Delta-like 1 (OP9-DL1) optimize Flt3L-driven development of cDC1 from murine immortalized progenitors and primary bone marrow cells. Co-culture with OP9-DL1 induced IRF8-dependent cDC1 with the phenotype (CD103+ Dec205+ CD8α+) and expression profile resembling ex vivo cDC1. OP9-DL1-induced cDC1 showed preferential migration towards Ccr7 ligands in vitro and superior T cell cross-priming and antitumor vaccination in vivo. Co-culture with OP9-DL1 also greatly increased the yield of IRF8-dependent CD141+ cDC1 from human bone marrow progenitors cultured with Flt3L. Thus, Notch signaling optimizes cDC generation in vitro and yields authentic cDC1 for functional studies and therapeutic applications.

ORGANISM(S): Mus musculus

PROVIDER: GSE110577 | GEO | 2018/06/05

REPOSITORIES: GEO

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Flt3L therapy induces a Treg‐promoting cDC1 state in triple‐negative breast cancer

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2022-06-21 | GSE168477 | GEO

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Project description:Purpose: Deficiency of Zbtb1 leads to the generation of myeloid cells from lymphoid progenitors when cultured in conditions that do not support myeloid development. We therefore analyzed how was the transcriptional signature altered by Zbtb1 deficiency in lymphoid progenitors ex vivo and after induction of a T-cell developmental program by co-culture with OP9-DL1 stroma cells.

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2023-03-01 | GSE198651 | GEO

Batf3 maintains Irf8 autoactivation for commitment of a novel clonogenic progenitor of CD8+DCs

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A Notch ligand, Delta-like 1 functions as an adhesion molecule for mast cells

Project description:To assess the effect of over-expression of Delta-like 1 on OP9 cells on gene expression in terms of Notch signaling and adhesion molecules, gene expressions of OP9, OP9-GFP (carrying GFP gene) and OP9-DL1 (carrying GFP and DL1 gene) cells (Immunity 2002;17:749-756) were analyzed.

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ATAC-seq of dendritic cell progenitors

Project description:Induction of the transcription factor Irf8 in the common dendritic cell progenitor (CDP) is required for classical type 1 dendritic cell (cDC1) fate specification, but the mechanisms controlling this induction are unclear. Here we identified Irf8 enhancers and used CRISPR/Cas9 genome editing to assess their roles in Irf8 regulation. An enhancer 32 kilobases downstream of the Irf8 transcriptional start site (+32 kb Irf8) that was active in mature cDC1s was required for the development of this lineage, but not for its specification. Instead, a +41 kb Irf8 enhancer previously thought to be active only in plasmacytoid DCs (pDCs) was found to also be transiently accessible in cDC1 progenitors. Deletion of this enhancer reduced Irf8 expression in pDCs as expected, but also surprisingly prevented the induction of Irf8 in CDPs and abolished cDC1 specification. Thus, cryptic activation of the +41 kb Irf8 enhancer in DC progenitors is responsible for cDC1 fate specification.

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Histone ChIP-seq of dendritic cell progenitors

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Optimization of the Irf8 +32 kb enhancer disrupts dendritic cell lineage segregation

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