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

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


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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Cell Differentiation
  • Cell Lineage
  • Dendritic Cells / cytology
  • Dendritic Cells / drug effects
  • Dendritic Cells / immunology*
  • Gene Expression Profiling
  • Gene Expression Regulation
  • Granulocyte-Macrophage Colony-Stimulating Factor / pharmacology
  • Humans
  • Immunophenotyping
  • Interleukin-4 / genetics
  • Interleukin-4 / immunology*
  • Interleukin-4 / pharmacology
  • Macrophage Activation
  • Macrophage Colony-Stimulating Factor / pharmacology
  • Macrophages / cytology
  • Macrophages / drug effects
  • Macrophages / immunology*
  • Monocytes / cytology
  • Monocytes / drug effects
  • Monocytes / immunology*
  • Nuclear Receptor Co-Repressor 2 / genetics
  • Nuclear Receptor Co-Repressor 2 / immunology*
  • Primary Cell Culture
  • Signal Transduction / immunology*
  • Time Factors
  • Transcription, Genetic


  • IL4 protein, human
  • NCOR2 protein, human
  • Nuclear Receptor Co-Repressor 2
  • Interleukin-4
  • Macrophage Colony-Stimulating Factor
  • Granulocyte-Macrophage Colony-Stimulating Factor