Immunity
Volume 47, Issue 6, 19 December 2017, Pages 1051-1066.e12
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Article
Cellular Differentiation of Human Monocytes Is Regulated by Time-Dependent Interleukin-4 Signaling and the Transcriptional Regulator NCOR2

https://doi.org/10.1016/j.immuni.2017.11.024Get rights and content
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Highlights

  • In vitro monocyte cultures model in vivo inflammatory dendritic cells and macrophages

  • Monocyte-derived dendritic cells integrate interleukin-4 signaling time dependently

  • NCOR2 controls differentiation of in vitro generated monocyte-derived dendritic cells

  • In vitro generated monocyte-derived cells are phenotypically heterogeneous

Summary

Human in vitro generated monocyte-derived dendritic cells (moDCs) and macrophages are used clinically, e.g., to induce immunity against cancer. However, their physiological counterparts, ontogeny, transcriptional regulation, and heterogeneity remains largely unknown, hampering their clinical use. High-dimensional techniques were used to elucidate transcriptional, phenotypic, and functional differences between human in vivo and in vitro generated mononuclear phagocytes to facilitate their full potential in the clinic. We demonstrate that monocytes differentiated by macrophage colony-stimulating factor (M-CSF) or granulocyte macrophage colony-stimulating factor (GM-CSF) resembled in vivo inflammatory macrophages, while moDCs resembled in vivo inflammatory DCs. Moreover, differentiated monocytes presented with profound transcriptomic, phenotypic, and functional differences. Monocytes integrated GM-CSF and IL-4 stimulation combinatorically and temporally, resulting in a mode- and time-dependent differentiation relying on NCOR2. Finally, moDCs are phenotypically heterogeneous and therefore necessitate the use of high-dimensional phenotyping to open new possibilities for better clinical tailoring of these cellular therapies.

Keywords

IL-4
human
monocytes
monocyte-derived dendritic cells
macrophages
IL-4 activated macrophages
M(IL-4)
activation
NCOR2
inflammatory dendritic cells
inflammatory macrophages

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These authors contributed equally

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