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Genomic programming of IRF4-expressing human Langerhans cells.
Sirvent, Sofia; Vallejo, Andres F; Davies, James; Clayton, Kalum; Wu, Zhiguo; Woo, Jeongmin; Riddell, Jeremy; Chaudhri, Virendra K; Stumpf, Patrick; Nazlamova, Liliya Angelova; Wheway, Gabrielle; Rose-Zerilli, Matthew; West, Jonathan; Pujato, Mario; Chen, Xiaoting; Woelk, Christopher H; MacArthur, Ben; Ardern-Jones, Michael; Friedmann, Peter S; Weirauch, Matthew T; Singh, Harinder; Polak, Marta E.
Affiliation
  • Sirvent S; Clinical and Experimental Sciences, Sir Henry Wellcome Laboratories, Faculty of Medicine, University of Southampton, SO16 6YD, Southampton, UK.
  • Vallejo AF; Clinical and Experimental Sciences, Sir Henry Wellcome Laboratories, Faculty of Medicine, University of Southampton, SO16 6YD, Southampton, UK.
  • Davies J; Clinical and Experimental Sciences, Sir Henry Wellcome Laboratories, Faculty of Medicine, University of Southampton, SO16 6YD, Southampton, UK.
  • Clayton K; Clinical and Experimental Sciences, Sir Henry Wellcome Laboratories, Faculty of Medicine, University of Southampton, SO16 6YD, Southampton, UK.
  • Wu Z; Division of Immunobiology & Center for Systems Immunology, Cincinnati Children's Hospital Medical Center, Cincinnati, OH, 45229, USA.
  • Woo J; Samsung Genome Institute, Samsung Medical Center, Seoul, South Korea.
  • Riddell J; Center for Autoimmune Genomics and Etiology, Cincinnati Children's Hospital Medical Center, Cincinnati, OH, 45229, USA.
  • Chaudhri VK; Division of Immunobiology & Center for Systems Immunology, Cincinnati Children's Hospital Medical Center, Cincinnati, OH, 45229, USA.
  • Stumpf P; Center for Systems Immunology, Departments of Immunology and Computational and Systems Biology, The University of Pittsburgh, Pittsburgh, PA, 15213, USA.
  • Nazlamova LA; Human Development and Health, Faculty of Medicine, University of Southampton, SO17 1BJ, Southampton, UK.
  • Wheway G; Clinical and Experimental Sciences, Sir Henry Wellcome Laboratories, Faculty of Medicine, University of Southampton, SO16 6YD, Southampton, UK.
  • Rose-Zerilli M; Human Development and Health, Faculty of Medicine, University of Southampton, SO17 1BJ, Southampton, UK.
  • West J; Cancer Sciences, Faculty of Medicine, University of Southampton, SO16 6YD, Southampton, UK.
  • Pujato M; Cancer Sciences, Faculty of Medicine, University of Southampton, SO16 6YD, Southampton, UK.
  • Chen X; Institute for Life Sciences, University of Southampton, SO17 1BJ, Southampton, UK.
  • Woelk CH; Division of Biomedical Informatics, Cincinnati Children's Hospital Medical Center, Cincinnati, OH, 45229, USA.
  • MacArthur B; Center for Autoimmune Genomics and Etiology, Cincinnati Children's Hospital Medical Center, Cincinnati, OH, 45229, USA.
  • Ardern-Jones M; Merck's Exploratory Science Center, Cambridge, MA, 02141, USA.
  • Friedmann PS; Cancer Sciences, Faculty of Medicine, University of Southampton, SO16 6YD, Southampton, UK.
  • Weirauch MT; Institute for Life Sciences, University of Southampton, SO17 1BJ, Southampton, UK.
  • Singh H; Clinical and Experimental Sciences, Sir Henry Wellcome Laboratories, Faculty of Medicine, University of Southampton, SO16 6YD, Southampton, UK.
  • Polak ME; Clinical and Experimental Sciences, Sir Henry Wellcome Laboratories, Faculty of Medicine, University of Southampton, SO16 6YD, Southampton, UK.
Nat Commun ; 11(1): 313, 2020 01 16.
Article in En | MEDLINE | ID: mdl-31949143
Langerhans cells (LC) can prime tolerogenic as well as immunogenic responses in skin, but the genomic states and transcription factors (TF) regulating these context-specific responses are unclear. Bulk and single-cell transcriptional profiling demonstrates that human migratory LCs are robustly programmed for MHC-I and MHC-II antigen presentation. Chromatin analysis reveals enrichment of ETS-IRF and AP1-IRF composite regulatory elements in antigen-presentation genes, coinciding with expression of the TFs, PU.1, IRF4 and BATF3 but not IRF8. Migration of LCs from the epidermis is accompanied by upregulation of IRF4, antigen processing components and co-stimulatory molecules. TNF stimulation augments LC cross-presentation while attenuating IRF4 expression. CRISPR-mediated editing reveals IRF4 to positively regulate the LC activation programme, but repress NF2EL2 and NF-kB pathway genes that promote responsiveness to oxidative stress and inflammatory cytokines. Thus, IRF4-dependent genomic programming of human migratory LCs appears to enable LC maturation while attenuating excessive inflammatory and immunogenic responses in the epidermis.
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Full text: 1 Collection: 01-internacional Database: MEDLINE Main subject: Langerhans Cells / Genomics / Interferon Regulatory Factors Limits: Humans Language: En Journal: Nat Commun Year: 2020 Document type: Article
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Full text: 1 Collection: 01-internacional Database: MEDLINE Main subject: Langerhans Cells / Genomics / Interferon Regulatory Factors Limits: Humans Language: En Journal: Nat Commun Year: 2020 Document type: Article