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

      research-article
      1 , 15 , 2 , 15 , 3 , 4 , 5 , 1 , 1 , 1 , 6 , 7 , 8 , 1 , 1 , 1 , 4 , 2 , 1 , 1 , 1 , 1 , 1 , 1 , 3 , 1 , 1 , 2 , 2 , 9 , 10 , 1 , 1 , 7 , 1 , 11 , 12 , 13 , 6 , 8 , 4 , 4 , 3 , 4 , 15 , 16 , , 1 , 14 , 15
      Immunity
      Cell Press
      IL-4, human, monocytes, monocyte-derived dendritic cells, macrophages, IL-4 activated macrophages, M(IL-4), activation, NCOR2, inflammatory dendritic cells, 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.

          Highlights

          • 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

          Abstract

          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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          Most cited references36

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          Tissue-Resident Macrophage Ontogeny and Homeostasis.

          Defining the origins and developmental pathways of tissue-resident macrophages should help refine our understanding of the role of these cells in various disease settings and enable the design of novel macrophage-targeted therapies. In recent years the long-held belief that macrophage populations in the adult are continuously replenished by monocytes from the bone marrow (BM) has been overturned with the advent of new techniques to dissect cellular ontogeny. The new paradigm suggests that several tissue-resident macrophage populations are seeded during waves of embryonic hematopoiesis and self-maintain independently of BM contribution during adulthood. However, the exact nature of the embryonic progenitors that give rise to adult tissue-resident macrophages is still debated, and the mechanisms enabling macrophage population maintenance in the adult are undefined. Here, we review the emergence of these concepts and discuss current controversies and future directions in macrophage biology.
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            Identification of DC-SIGN, a novel dendritic cell-specific ICAM-3 receptor that supports primary immune responses.

            Contact between dendritic cells (DC) and resting T cells is essential to initiate a primary immune response. Here, we demonstrate that ICAM-3 expressed by resting T cells is important in this first contact with DC. We discovered that instead of the common ICAM-3 receptors LFA-1 and alphaDbeta2, a novel DC-specific C-type lectin, DC-SIGN, binds ICAM-3 with high affinity. DC-SIGN, which is abundantly expressed by DC both in vitro and in vivo, mediates transient adhesion with T cells. Since antibodies against DC-SIGN inhibit DC-induced proliferation of resting T cells, our findings predict that DC-SIGN enables T cell receptor engagement by stabilization of the DC-T cell contact zone.
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              An environment-dependent transcriptional network specifies human microglia identity

              Microglia play essential roles in central nervous system (CNS) homeostasis and influence diverse aspects of neuronal function. However, the transcriptional mechanisms that specify human microglia phenotypes are largely unknown. We examined the transcriptomes and epigenetic landscapes of human microglia isolated from surgically resected brain tissue ex vivo and following transition to an in vitro environment. Transfer to a tissue culture environment results in rapid and extensive downregulation of microglia-specific genes that are induced in primitive mouse macrophages following migration into the fetal brain. Substantial subsets of these genes exhibit altered expression in neurodegenerative and behavioral diseases and are associated with non-coding risk variants. These findings reveal an environment-dependent transcriptional network specifying microglia-specific programs of gene expression and facilitate efforts to understand the roles of microglia in human disease.
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                Author and article information

                Contributors
                Journal
                Immunity
                Immunity
                Immunity
                Cell Press
                1074-7613
                1097-4180
                19 December 2017
                19 December 2017
                : 47
                : 6
                : 1051-1066.e12
                Affiliations
                [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
                [5 ]Department of Pathology and Center for Trophoblast Research, University of Cambridge, CB2 1QP Cambridge, UK
                [6 ]Cellular Immunology, LIMES-Institute, University of Bonn, 53115 Bonn, Germany
                [7 ]Molecular Immunology & Cell Biology, LIMES-Institute, University of Bonn, 53115 Bonn, Germany
                [8 ]Department of Materials Science and Engineering, Stanford University, Stanford, CA 94305, USA
                [9 ]Department of Medicine, University of Massachusetts Medical School, Worcester, MA 01605, USA
                [10 ]German Center for Neurodegenerative Diseases, 53127 Bonn, Germany
                [11 ]Molecular Immunology, German Center for Neurodegenerative Diseases (DZNE), Sigmund-Freud-Str. 27, 53127 Bonn, Germany
                [12 ]Institute of Transplant Immunology, Integrated Research and Treatment Center Transplantation, Hannover Medical School, 30625 Hannover, Germany
                [13 ]Department of Cardiothoracic, Transplantation and Vascular Surgery, Hannover Medical School, 30625 Hannover, Germany
                [14 ]Platform for Single Cell Genomics and Epigenomics (PRECISE) at the German Center for Neurodegenerative Diseases and the University of Bonn, 53127 Bonn, Germany
                Author notes
                []Corresponding author andreas.schlitzer@ 123456uni-bonn.de
                [15]

                These authors contributed equally

                [16]

                Lead Contact

                Article
                S1074-7613(17)30525-3
                10.1016/j.immuni.2017.11.024
                5772172
                29262348
                ab1edb97-784e-4b79-b848-4a76ae2d3182
                © 2017 The Authors. Published by Elsevier Inc.

                This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/).

                History
                : 31 March 2017
                : 15 September 2017
                : 28 November 2017
                Categories
                Article

                Immunology
                il-4,human,monocytes,monocyte-derived dendritic cells,macrophages,il-4 activated macrophages,m(il-4),activation,ncor2,inflammatory dendritic cells,inflammatory macrophages

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