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Immunity. 2017 Dec 19;47(6):1051-1066.e12. doi: 10.1016/j.immuni.2017.11.024.

Cellular Differentiation of Human Monocytes Is Regulated by Time-Dependent Interleukin-4 Signaling and the Transcriptional Regulator NCOR2.

Author information

1
Genomics and Immunoregulation, LIMES-Institute, University of Bonn, 53115 Bonn, Germany.
2
Institute of Innate Immunity, University Hospital Bonn, University of Bonn, Sigmund-Freud-Strasse 25, 53127 Bonn, Germany.
3
Myeloid Cell Biology, LIMES-Institute, University of Bonn, 53115 Bonn, Germany.
4
Agency for Science, Technology and Research (A(∗)STAR), Singapore Immunology Network (SIgN), 138648 Singapore, Singapore; Department of Pathology and Center for Trophoblast Research, University of Cambridge, CB2 1QP Cambridge, UK.
5
Cellular Immunology, LIMES-Institute, University of Bonn, 53115 Bonn, Germany.
6
Molecular Immunology & Cell Biology, LIMES-Institute, University of Bonn, 53115 Bonn, Germany.
7
Department of Materials Science and Engineering, Stanford University, Stanford, CA 94305, USA.
8
Agency for Science, Technology and Research (A(∗)STAR), Singapore Immunology Network (SIgN), 138648 Singapore, Singapore.
9
Institute of Innate Immunity, University Hospital Bonn, University of Bonn, Sigmund-Freud-Strasse 25, 53127 Bonn, Germany; Department of Medicine, University of Massachusetts Medical School, Worcester, MA 01605, USA; German Center for Neurodegenerative Diseases, 53127 Bonn, Germany.
10
Genomics and Immunoregulation, LIMES-Institute, University of Bonn, 53115 Bonn, Germany; Molecular Immunology, German Center for Neurodegenerative Diseases (DZNE), Sigmund-Freud-Str. 27, 53127 Bonn, Germany.
11
Institute of Transplant Immunology, Integrated Research and Treatment Center Transplantation, Hannover Medical School, 30625 Hannover, Germany.
12
Department of Cardiothoracic, Transplantation and Vascular Surgery, Hannover Medical School, 30625 Hannover, Germany.
13
Myeloid Cell Biology, LIMES-Institute, University of Bonn, 53115 Bonn, Germany; Agency for Science, Technology and Research (A(∗)STAR), Singapore Immunology Network (SIgN), 138648 Singapore, Singapore. Electronic address: andreas.schlitzer@uni-bonn.de.
14
Genomics and Immunoregulation, LIMES-Institute, University of Bonn, 53115 Bonn, Germany; Platform for Single Cell Genomics and Epigenomics (PRECISE) at the German Center for Neurodegenerative Diseases and the University of Bonn, 53127 Bonn, Germany.

Abstract

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

PMID:
29262348
PMCID:
PMC5772172
DOI:
10.1016/j.immuni.2017.11.024
[Indexed for MEDLINE]
Free PMC Article

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