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

Lookup NU author(s): Dr Urszula Cytlak-Chaudhuri, Anastasia Resteu, Professor Matthew Collin, Dr Venetia Bigley

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This work is licensed under a Creative Commons Attribution 4.0 International License (CC BY 4.0).


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+CD8+) and expression profile resembling primary splenic 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 translational applications.


Publication metadata

Author(s): Kirkling ME, Cytlak U, Lau CM, Lewis KL, Resteu A, Khodadadi-Jamayran A, Siebel CW, Salmon H, Merad M, Tsirigos A, Collin M, Bigley V, Reizis B

Publication type: Article

Publication status: Published

Journal: Cell Reports

Year: 2018

Volume: 23

Issue: 12

Pages: 3658-3672.e6

Print publication date: 19/06/2018

Online publication date: 19/06/2018

Acceptance date: 18/05/2018

Date deposited: 21/05/2018

ISSN (electronic): 2211-1247

Publisher: Cell Press

URL: https://doi.org/10.1016/j.celrep.2018.05.068

DOI: 10.1016/j.celrep.2018.05.068


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