title: Human skin dendritic cell fate is differentially regulated by the monocyte identity factor Kruppel-like factor 4 during steady state and inflammation.
abstract: BACKGROUND
  Langerhans cell (LC) networks play key roles in immunity and tolerance at body surfaces. LCs are established prenatally and can be replenished from blood monocytes. Unlike skin-resident dermal DCs (dDCs)/interstitial-type DCs and inflammatory dendritic epidermal cells appearing in dermatitis/eczema lesions, LCs lack key monocyte-affiliated markers. Inversely, LCs express various epithelial genes critical for their long-term peripheral tissue residency.
  
  
  OBJECTIVE
  Dendritic cells (DCs) are functionally involved in inflammatory diseases; however, the mechanisms remained poorly understood.
  
  
  METHODS
  In vitro differentiation models of human DCs, gene profiling, gene transduction, and immunohistology were used to identify molecules involved in DC subset specification.
  
  
  RESULTS
  Here we identified the monocyte/macrophage lineage identity transcription factor Kruppel-like factor 4 (KLF4) to be inhibited during LC differentiation from human blood monocytes. Conversely, KLF4 is maintained or induced during dermal DC and monocyte-derived dendritic cell/inflammatory dendritic epidermal cell differentiation. We showed that in monocytic cells KLF4 has to be repressed to allow their differentiation into LCs. Moreover, respective KLF4 levels in DC subsets positively correlate with proinflammatory characteristics. We identified epithelial Notch signaling to repress KLF4 in monocytes undergoing LC commitment. Loss of KLF4 in monocytes transcriptionally derepresses Runt-related transcription factor 3 in response to TGF-β1, thereby allowing LC differentiation marked by a low cytokine expression profile.
  
  
  CONCLUSIONS
  Monocyte differentiation into LCs depends on activation of Notch signaling and the concomitant loss of KLF4.
authors.affiliation: Institute of Immunology, Medical University of Vienna, Vienna, Austria.
authors.forename: Jennifer
authors.initials: J
authors.lastname: Jurkin
authors.affiliation: Institute of Pathophysiology and Immunology, Medical University of Graz, Graz, Austria.
authors.forename: Corinna
authors.initials: C
authors.lastname: Krump
authors.affiliation: Institute of Immunology, Medical University of Vienna, Vienna, Austria.
authors.forename: René
authors.initials: R
authors.lastname: Köffel
authors.affiliation: Institute of Immunology, Medical University of Vienna, Vienna, Austria.
authors.forename: Christina
authors.initials: C
authors.lastname: Fieber
authors.affiliation: Division of Immunology, Allergy and Infectious Diseases, Department of Dermatology, Medical University of Vienna, Vienna, Austria.
authors.forename: Christopher
authors.initials: C
authors.lastname: Schuster
authors.affiliation: Division of Immunology, Allergy and Infectious Diseases, Department of Dermatology, Medical University of Vienna, Vienna, Austria.
authors.forename: Patrick M
authors.initials: PM
authors.lastname: Brunner
authors.affiliation: Institute of Pathophysiology and Immunology, Medical University of Graz, Graz, Austria.
authors.forename: Izabela
authors.initials: I
authors.lastname: Borek
authors.affiliation: Institute of Immunology, Medical University of Vienna, Vienna, Austria.
authors.forename: Gregor
authors.initials: G
authors.lastname: Eisenwort
authors.affiliation: Institute of Pathophysiology and Immunology, Medical University of Graz, Graz, Austria; Institute of Immunology, Medical University of Vienna, Vienna, Austria.
authors.forename: Clarice
authors.initials: C
authors.lastname: Lim
authors.affiliation: Institute of Clinical Microbiology, Immunology and Hygiene, University Hospital Erlangen, Friedrich-Alexander-University Erlangen-Nürnberg, Erlangen, Germany.
authors.forename: Jörg
authors.initials: J
authors.lastname: Mages
authors.affiliation: Institute of Clinical Microbiology, Immunology and Hygiene, University Hospital Erlangen, Friedrich-Alexander-University Erlangen-Nürnberg, Erlangen, Germany.
authors.forename: Roland
authors.initials: R
authors.lastname: Lang
authors.affiliation: Division of Immunology, Allergy and Infectious Diseases, Department of Dermatology, Medical University of Vienna, Vienna, Austria.
authors.forename: Wolfgang
authors.initials: W
authors.lastname: Bauer
authors.affiliation: Departments of Pathophysiology and Allergy Research, Medical University of Vienna, Vienna, Austria.
authors.forename: Diana
authors.initials: D
authors.lastname: Mechtcheriakova
authors.affiliation: Departments of Pathophysiology and Allergy Research, Medical University of Vienna, Vienna, Austria.
authors.forename: Anastasia
authors.initials: A
authors.lastname: Meshcheryakova
authors.affiliation: Division of Immunology, Allergy and Infectious Diseases, Department of Dermatology, Medical University of Vienna, Vienna, Austria.
authors.forename: Adelheid
authors.initials: A
authors.lastname: Elbe-Bürger
authors.affiliation: Division of Immunology, Allergy and Infectious Diseases, Department of Dermatology, Medical University of Vienna, Vienna, Austria.
authors.forename: Georg
authors.initials: G
authors.lastname: Stingl
authors.affiliation: Institute of Pathophysiology and Immunology, Medical University of Graz, Graz, Austria; Institute of Immunology, Medical University of Vienna, Vienna, Austria. Electronic address: herbert.strobl@medunigraz.at.
authors.forename: Herbert
authors.initials: H
authors.lastname: Strobl
mesh_terms: D000328:Adult; D002454:Cell Differentiation / Q000502:physiology; D002478:Cells, Cultured; D003713:Dendritic Cells / Q000166:cytology* / Q000378:metabolism; D004622:Embryo, Mammalian; D005312:Fetal Blood / Q000166:cytology; D006801:Humans; D007249:Inflammation / Q000378:metabolism; D000090062:Kruppel-Like Factor 4; D051741:Kruppel-Like Transcription Factors / Q000378:metabolism*; D009000:Monocytes / Q000166:cytology* / Q000378:metabolism; D012867:Skin / Q000166:cytology*; D053773:Transforming Growth Factor beta1 / Q000494:pharmacology
chemical_list: C000715467:KLF4 protein, human; D000090062:Kruppel-Like Factor 4; D051741:Kruppel-Like Transcription Factors; D053773:Transforming Growth Factor beta1
keywords: Kruppel-like factor 4; Notch; Runt-related transcription factor 3; TGF-β1 signaling; lineage decision; monocyte differentiation