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Blood Adv. 2017 Jun 7;1(14):947-960. doi: 10.1182/bloodadvances.2017006858. eCollection 2017 Jun 13.

Novel GM-CSF signals via IFN-γR/IRF-1 and AKT/mTOR license monocytes for suppressor function.

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Institute for Virology and Immunobiology, University of Würzburg, Würzburg, Germany.
Section of Experimental Surgery, Department of Surgery, University of Regensburg, Regensburg, Germany.
Rudolf Virchow Center, Research Center for Experimental Biomedicine, University of Würzburg, Würzburg, Germany.
Department of Internal Medicine II, University Hospital Würzburg, Würzburg, Germany.
Microbiology Institute-Clinical Microbiology, Immunology and Hygiene, Universitätsklinikum Erlangen, Friedrich-Alexander-Universität Erlangen-Nürnberg, Erlangen, Germany.
Stem Cell Laboratory, University Children's Hospital Würzburg, University of Würzburg, Würzburg, Germany; and.
Institute of Medical Microbiology and Hygiene, University of Marburg, Marburg, Germany.


Granulocyte-macrophage colony-stimulating factor (GM-CSF) controls proliferation and survival of myeloid cells including monocytes. Here, we describe a time-dependent licensing process driven by GM-CSF in murine Ly6Chigh and human CD14+ monocytes that disables their inflammatory functions and promotes their conversion into suppressor cells. This 2-step licensing of monocytes requires activation of the AKT/mTOR/mTORC1 signaling cascade by GM-CSF followed by signaling through the interferon-γ receptor (IFN-γR)/interferon regulatory factor-1 (IRF-1) pathway. Only licensing-dependent adaptations in Toll-like receptor/inflammasome, IFN-γR, and phosphatidylinositol 3-kinase/AKT/mTOR signaling lead to stabilized expression of inducible nitric oxide synthase by mouse and indoleamine 2,3-dioxygenase (IDO) by human monocytes, which accounts for their suppressor activity. This study suggests various myeloid cells with characteristics similar to those described for monocytic myeloid-derived suppressor cells, Mreg, or suppressor macrophages may arise from licensed monocytes. Markers of GM-CSF-driven monocyte licensing, including p-Akt, p-mTOR, and p-S6, distinguish inflammatory monocytes from potentially suppressive monocytes in peripheral blood of patients with high-grade glioma.

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