Genomic programming of IRF4-expressing human Langerhans cells

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, Matthew Rose-Zerilli, Jonathan West, Mario Pujato, Xiaoting Chen, Christopher H. Woelk, Ben MacArthur, Michael Ardern-Jones, Peter S. Friedmann, Matthew T. Weirauch, Harinder Singh () and Marta E. Polak ()
Additional contact information
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
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
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
Michael Ardern-Jones: University of Southampton
Peter S. Friedmann: University of Southampton
Matthew T. Weirauch: Cincinnati Children’s Hospital Medical Center
Harinder Singh: Cincinnati Children’s Hospital Medical Center
Marta E. Polak: University of Southampton

Nature Communications, 2020, vol. 11, issue 1, 1-12

Abstract: 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.

Date: 2020
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DOI: 10.1038/s41467-019-14125-x

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