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

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. Hi...

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Bibliographic Details
Published in:	Immunity (Cambridge, Mass.) Vol. 47; no. 6; pp. 1051 - 1066.e12
Main Authors:	Sander, Jil, Schmidt, Susanne V., Cirovic, Branko, McGovern, Naomi, Papantonopoulou, Olympia, Hardt, Anna-Lena, Aschenbrenner, Anna C., Kreer, Christoph, Quast, Thomas, Xu, Alexander M., Schmidleithner, Lisa M., Theis, Heidi, Thi Huong, Lan Do, Sumatoh, Hermi Rizal Bin, Lauterbach, Mario A.R., Schulte-Schrepping, Jonas, Günther, Patrick, Xue, Jia, Baßler, Kevin, Ulas, Thomas, Klee, Kathrin, Katzmarski, Natalie, Herresthal, Stefanie, Krebs, Wolfgang, Martin, Bianca, Latz, Eicke, Händler, Kristian, Kraut, Michael, Kolanus, Waldemar, Beyer, Marc, Falk, Christine S., Wiegmann, Bettina, Burgdorf, Sven, Melosh, Nicholas A., Newell, Evan W., Ginhoux, Florent, Schlitzer, Andreas, Schultze, Joachim L.
Format:	Journal Article
Language:	English
Published:	United States Elsevier Inc 19-12-2017 Elsevier Limited Cell Press
Subjects:	activation Bone marrow Cancer Cell Differentiation Cell Lineage Cellular biology Chemokines Colonies Colony-stimulating factor Dendritic cells Dendritic Cells - cytology Dendritic Cells - drug effects Dendritic Cells - immunology Differentiation (biology) Gene Expression Profiling Gene Expression Regulation Gene regulation Granulocyte-macrophage colony-stimulating factor Granulocyte-Macrophage Colony-Stimulating Factor - pharmacology human Humanin Humans IL-4 IL-4 activated macrophages Immunity Immunophenotyping inflammatory dendritic cells inflammatory macrophages Interleukin 4 Interleukin-4 - genetics Interleukin-4 - immunology Interleukin-4 - pharmacology Leukocytes (mononuclear) M(IL-4) Macrophage Activation Macrophage Colony-Stimulating Factor - pharmacology Macrophages Macrophages - cytology Macrophages - drug effects Macrophages - immunology monocyte-derived dendritic cells Monocytes Monocytes - cytology Monocytes - drug effects Monocytes - immunology NCOR2 Nuclear Receptor Co-Repressor 2 - genetics Nuclear Receptor Co-Repressor 2 - immunology Ontogeny Phagocytes Phenotyping Primary Cell Culture Signal Transduction - immunology Signaling Specialization Time dependence Time Factors Transcription Transcription, Genetic NCOR2 monocytes macrophages IL-4 activated macrophages inflammatory dendritic cells IL-4 activation human monocyte-derived dendritic cells M(IL-4) inflammatory macrophages
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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. •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 Monocyte-derived cellular derivatives are used clinically and are a crucial tool in basic research. Sander and colleagues now show that they transcriptionally relate to in vivo inflammatory monocytes, that they integrate differentiation cues time dependently, and that in vitro differentiated monocytes are phenotypically heterogeneous.
Bibliography:	ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 23 Lead Contact These authors contributed equally
ISSN:	1074-7613 1097-4180
DOI:	10.1016/j.immuni.2017.11.024