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

Publication date: 19 December 2017
Source:Immunity, Volume 47, Issue 6
Author(s): Jil Sander, Susanne V. Schmidt, Branko Cirovic, Naomi McGovern, Olympia Papantonopoulou, Anna-Lena Hardt, Anna C. Aschenbrenner, Christoph Kreer, Thomas Quast, Alexander M. Xu, Lisa M. Schmidleithner, Heidi Theis, Lan Do Thi Huong, Hermi Rizal Bin Sumatoh, Mario A.R. Lauterbach, Jonas Schulte-Schrepping, Patrick Günther, Jia Xue, Kevin Baßler, Thomas Ulas, Kathrin Klee, Natalie Katzmarski, Stefanie Herresthal, Wolfgang Krebs, Bianca Martin, Eicke Latz, Kristian Händler, Michael Kraut, Waldemar Kolanus, Marc Beyer, Christine S. Falk, Bettina Wiegmann, Sven Burgdorf, Nicholas A. Melosh, Evan W. Newell, Florent Ginhoux, Andreas Schlitzer, Joachim L. Schultze
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.

Teaser

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.


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