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Genomic programming of IRF4-expressing human Langerhans cells

Author

Listed:
  • Sofia Sirvent

    (University of Southampton)

  • Andres F. Vallejo

    (University of Southampton)

  • James Davies

    (University of Southampton)

  • Kalum Clayton

    (University of Southampton)

  • Zhiguo Wu

    (Cincinnati Children’s Hospital Medical Center)

  • Jeongmin Woo

    (Samsung Medical Center)

  • Jeremy Riddell

    (Cincinnati Children’s Hospital Medical Center)

  • Virendra K. Chaudhri

    (Cincinnati Children’s Hospital Medical Center
    The University of Pittsburgh)

  • Patrick Stumpf

    (University of Southampton)

  • Liliya Angelova Nazlamova

    (University of Southampton)

  • Gabrielle Wheway

    (University of Southampton)

  • Matthew Rose-Zerilli

    (University of Southampton)

  • Jonathan West

    (University of Southampton
    University of Southampton)

  • Mario Pujato

    (Cincinnati Children’s Hospital Medical Center)

  • Xiaoting Chen

    (Cincinnati Children’s Hospital Medical Center)

  • Christopher H. Woelk

    (Merck’s Exploratory Science Center)

  • Ben MacArthur

    (University of Southampton
    University of Southampton)

  • Michael Ardern-Jones

    (University of Southampton)

  • Peter S. Friedmann

    (University of Southampton)

  • Matthew T. Weirauch

    (Cincinnati Children’s Hospital Medical Center
    University of Cincinnati College of Medicine, Cincinnati)

  • Harinder Singh

    (Cincinnati Children’s Hospital Medical Center
    University of Cincinnati College of Medicine, Cincinnati
    The University of Pittsburgh)

  • Marta E. Polak

    (University of Southampton
    University of Southampton)

Abstract

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.

Suggested Citation

  • Sofia Sirvent & Andres F. Vallejo & James Davies & Kalum Clayton & Zhiguo Wu & Jeongmin Woo & Jeremy Riddell & Virendra K. Chaudhri & Patrick Stumpf & Liliya Angelova Nazlamova & Gabrielle Wheway & Ma, 2020. "Genomic programming of IRF4-expressing human Langerhans cells," Nature Communications, Nature, vol. 11(1), pages 1-12, December.
    • Handle: RePEc:nat:natcom:v:11:y:2020:i:1:d:10.1038_s41467-019-14125-x
    DOI: 10.1038/s41467-019-14125-x
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    Cited by:

    1. Sofia Sirvent & Andres F. Vallejo & Emma Corden & Ying Teo & James Davies & Kalum Clayton & Eleanor G. Seaby & Chester Lai & Sarah Ennis & Rfeef Alyami & Gemma Douilhet & Lareb S. N. Dean & Matthew Lo, 2023. "Impaired expression of metallothioneins contributes to allergen-induced inflammation in patients with atopic dermatitis," Nature Communications, Nature, vol. 14(1), pages 1-14, December.

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