title: Transcription factor IRF4 drives dendritic cells to promote Th2 differentiation.
abstract: Atopic asthma is an inflammatory pulmonary disease associated with Th2 adaptive immune responses triggered by innocuous antigens. While dendritic cells (DCs) are known to shape the adaptive immune response, the mechanisms by which DCs promote Th2 differentiation remain elusive. Herein we demonstrate that Th2-promoting stimuli induce DC expression of IRF4. Mice with conditional deletion of Irf4 in DCs show a dramatic defect in Th2-type lung inflammation, yet retain the ability to elicit pulmonary Th1 antiviral responses. Using loss- and gain-of-function analysis, we demonstrate that Th2 differentiation is dependent on IRF4 expression in DCs. Finally, IRF4 directly targets and activates the Il-10 and Il-33 genes in DCs. Reconstitution with exogenous IL-10 and IL-33 recovers the ability of Irf4-deficient DCs to promote Th2 differentiation. These findings reveal a regulatory module in DCs by which IRF4 modulates IL-10 and IL-33 cytokine production to specifically promote Th2 differentiation and inflammation.
authors.affiliation: Committee on Molecular Pathogenesis and Molecular Medicine, University of Chicago, 924 E. 57th Street, Chicago, Illinois 60637 USA.
authors.forename: Jesse W
authors.initials: JW
authors.lastname: Williams
authors.affiliation: 1] Committee on Immunology, University of Chicago, 924 E. 57th Street, Chicago, Illinois 60637 USA [2] Medical Scientist Training Program, University of Chicago, 924 E. 57th Street, Chicago, Illinois 60637 USA.
authors.forename: Melissa Y
authors.initials: MY
authors.lastname: Tjota
authors.affiliation: Committee on Immunology, University of Chicago, 924 E. 57th Street, Chicago, Illinois 60637 USA.
authors.forename: Bryan S
authors.initials: BS
authors.lastname: Clay
authors.affiliation: Department of Discovery Immunology, Genentech Inc., 1 DNA Way, South San Francisco, California 94080 USA.
authors.forename: Bryan
authors.initials: B
authors.lastname: Vander Lugt
authors.affiliation: Committee on Immunology, University of Chicago, 924 E. 57th Street, Chicago, Illinois 60637 USA.
authors.forename: Hozefa S
authors.initials: HS
authors.lastname: Bandukwala
authors.affiliation: Section of Pulmonary and Critical Care Medicine, Department of Medicine, University of Chicago, 924 E. 57th Street, Chicago, Illinois 60637 USA.
authors.forename: Cara L
authors.initials: CL
authors.lastname: Hrusch
authors.affiliation: Section of Pulmonary and Critical Care Medicine, Department of Medicine, University of Chicago, 924 E. 57th Street, Chicago, Illinois 60637 USA.
authors.forename: Donna C
authors.initials: DC
authors.lastname: Decker
authors.affiliation: Section of Pulmonary and Critical Care Medicine, Department of Medicine, University of Chicago, 924 E. 57th Street, Chicago, Illinois 60637 USA.
authors.forename: Kelly M
authors.initials: KM
authors.lastname: Blaine
authors.affiliation: Section of Pulmonary and Critical Care Medicine, Department of Medicine, University of Chicago, 924 E. 57th Street, Chicago, Illinois 60637 USA.
authors.forename: Bethany R
authors.initials: BR
authors.lastname: Fixsen
authors.affiliation: Department of Discovery Immunology, Genentech Inc., 1 DNA Way, South San Francisco, California 94080 USA.
authors.forename: Harinder
authors.initials: H
authors.lastname: Singh
authors.affiliation: Department of Surgery, University of Chicago, 5841 S. Maryland Avenue, Chicago, Illinois 60637 USA.
authors.forename: Roger
authors.initials: R
authors.lastname: Sciammas
authors.affiliation: 1] Committee on Molecular Pathogenesis and Molecular Medicine, University of Chicago, 924 E. 57th Street, Chicago, Illinois 60637 USA [2] Committee on Immunology, University of Chicago, 924 E. 57th Street, Chicago, Illinois 60637 USA [3] Section of Pulmonary and Critical Care Medicine, Department of Medicine, University of Chicago, 924 E. 57th Street, Chicago, Illinois 60637 USA.
authors.forename: Anne I
authors.initials: AI
authors.lastname: Sperling
mesh_terms: D000818:Animals; D001249:Asthma / Q000378:metabolism*; D001854:Bone Marrow Cells / Q000166:cytology; D002454:Cell Differentiation; D003713:Dendritic Cells / Q000166:cytology*; D005260:Female; D005786:Gene Expression Regulation; D006969:Hypersensitivity, Immediate / Q000378:metabolism*; D007249:Inflammation; D050835:Interferon Regulatory Factors / Q000378:metabolism*; D016753:Interleukin-10 / Q000378:metabolism; D007378:Interleukins; D008168:Lung / Q000378:metabolism*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D008925:Mites; D020411:Oligonucleotide Array Sequence Analysis; D015398:Signal Transduction; D018418:Th2 Cells / Q000166:cytology*; D000099218:Interferon Regulatory Factor-4
chemical_list: D050835:Interferon Regulatory Factors; D016753:Interleukin-10; D007378:Interleukins; D000099218:Interferon Regulatory Factor-4