IRF8 Transcription Factor Controls Survival and Function of Terminally Differentiated Conventional and Plasmacytoid Dendritic Cells, Respectively

Dorine Sichien; Charlotte L Scott; Liesbet Martens; Matthias Vanderkerken; Sofie Van Gassen; Maud Plantinga; Thorsten Joeris; Sofie De Prijck; Leen Vanhoutte; Manon Vanheerswynghels; Gert Van Isterdael; Wendy Toussaint; Filipe Branco Madeira; Karl Vergote; William W Agace; Björn E Clausen; Hamida Hammad; Marc Dalod; Yvan Saeys; Bart N Lambrecht; Martin Guilliams

doi:10.1016/j.immuni.2016.08.013

IRF8 Transcription Factor Controls Survival and Function of Terminally Differentiated Conventional and Plasmacytoid Dendritic Cells, Respectively

Immunity. 2016 Sep 20;45(3):626-640. doi: 10.1016/j.immuni.2016.08.013. Epub 2016 Sep 13.

Authors

Dorine Sichien¹, Charlotte L Scott¹, Liesbet Martens², Matthias Vanderkerken³, Sofie Van Gassen⁴, Maud Plantinga³, Thorsten Joeris⁵, Sofie De Prijck¹, Leen Vanhoutte⁶, Manon Vanheerswynghels³, Gert Van Isterdael³, Wendy Toussaint³, Filipe Branco Madeira³, Karl Vergote³, William W Agace⁷, Björn E Clausen⁸, Hamida Hammad³, Marc Dalod⁹, Yvan Saeys¹⁰, Bart N Lambrecht¹¹, Martin Guilliams¹²

Affiliations

¹ Lab of Immunoregulation, VIB Inflammation Research Center, Ghent University, 9052 Ghent, Belgium; Department of Biomedical Molecular Biology, Ghent University, 9052 Ghent, Belgium.
² Department of Respiratory Medicine, University Hospital Ghent, 9000 Ghent, Belgium; Data Mining and Modelling for Biomedicine Group, VIB Inflammation Research Center, Ghent University, 9052 Ghent, Belgium.
³ Lab of Immunoregulation, VIB Inflammation Research Center, Ghent University, 9052 Ghent, Belgium; Department of Respiratory Medicine, University Hospital Ghent, 9000 Ghent, Belgium.
⁴ Lab of Immunoregulation, VIB Inflammation Research Center, Ghent University, 9052 Ghent, Belgium; Data Mining and Modelling for Biomedicine Group, VIB Inflammation Research Center, Ghent University, 9052 Ghent, Belgium; Department of Information Technology, iMinds, Ghent University, Ghent, Belgium.
⁵ Section of Immunology and Vaccinology, Danish Technical University Veterinary Institute, 1870 Copenhagen, Denmark.
⁶ Lab of Immunoregulation, VIB Inflammation Research Center, Ghent University, 9052 Ghent, Belgium; Department of Medical Genetics, University Hospital Ghent, 9000 Ghent, Belgium.
⁷ Section of Immunology and Vaccinology, Danish Technical University Veterinary Institute, 1870 Copenhagen, Denmark; Department of Experimental Medical Science, Immunology Section, Lund University, 221 00 Lund, Sweden.
⁸ Institute for Molecular Medicine, University Medical Center of the Johannes Gutenberg-University Mainz, 55131 Mainz, Germany.
⁹ Centre d'Immunologie de Marseille-Luminy, UNIV UM2, Aix-Marseille Université, Parc Scientifique et Technologique de Luminy, 13288 Marseille, France; INSERM, U1104, 13288 Marseille, France; CNRS, UMR7280, 13288 Marseille, France.
¹⁰ Lab of Immunoregulation, VIB Inflammation Research Center, Ghent University, 9052 Ghent, Belgium; Department of Respiratory Medicine, University Hospital Ghent, 9000 Ghent, Belgium; Data Mining and Modelling for Biomedicine Group, VIB Inflammation Research Center, Ghent University, 9052 Ghent, Belgium.
¹¹ Lab of Immunoregulation, VIB Inflammation Research Center, Ghent University, 9052 Ghent, Belgium; Department of Respiratory Medicine, University Hospital Ghent, 9000 Ghent, Belgium; Department of Pulmonary Medicine, Erasmus MC, University Medical Center, Rotterdam, 3015 the Netherlands. Electronic address: bart.lambrecht@irc.vib-ugent.be.
¹² Lab of Immunoregulation, VIB Inflammation Research Center, Ghent University, 9052 Ghent, Belgium; Department of Biomedical Molecular Biology, Ghent University, 9052 Ghent, Belgium. Electronic address: martin.guilliams@irc.vib-ugent.be.

PMID: 27637148
DOI: 10.1016/j.immuni.2016.08.013

Abstract

Interferon regulatory factor-8 (IRF8) has been proposed to be essential for development of monocytes, plasmacytoid dendritic cells (pDCs) and type 1 conventional dendritic cells (cDC1s) and remains highly expressed in differentiated DCs. Transcription factors that are required to maintain the identity of terminally differentiated cells are designated "terminal selectors." Using BM chimeras, conditional Irf8(fl/fl) mice and various promotors to target Cre recombinase to different stages of monocyte and DC development, we have identified IRF8 as a terminal selector of the cDC1 lineage controlling survival. In monocytes, IRF8 was necessary during early but not late development. Complete or late deletion of IRF8 had no effect on pDC development or survival but altered their phenotype and gene-expression profile leading to increased T cell stimulatory function but decreased type 1 interferon production. Thus, IRF8 differentially controls the survival and function of terminally differentiated monocytes, cDC1s, and pDCs.

Keywords: IRF4; IRF8; dendritic cell; development; lineage; monocyte; plasmacytoid dendritic cell; terminal selector; transcription factor.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Animals
Cell Differentiation / physiology*
Dendritic Cells / metabolism*
Dendritic Cells / physiology*
Interferon Regulatory Factors / metabolism*
Interferon Type I / metabolism
Mice
Mice, Inbred C57BL
Monocytes / metabolism
Monocytes / physiology
Promoter Regions, Genetic / physiology
T-Lymphocytes / metabolism
T-Lymphocytes / physiology
Transcription Factors / metabolism*

Substances

Interferon Regulatory Factors
Interferon Type I
Transcription Factors
interferon regulatory factor-8