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Genomic programming of IRF4-expressing human Langerhans cells

Genomic programming of IRF4-expressing human Langerhans cells
Genomic programming of IRF4-expressing human Langerhans cells
Langerhans cells (LC) can prime tolerogenic as well as immunogenic responses in skin, but the genomic states and transcription factors (TFs) 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 program, 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.
2041-1723
Sirvent Bernal, Sofia
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Vallejo Pulido, Andres
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Davies, James
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Clayton, Kalum
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Wu, Zhiguo
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Woo, Jeongmin
cd0ede17-cc62-43ca-acbc-4b235a5a53a2
Riddell, Jeremy
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Chaudhri, Virendra K.
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Stumpf, Patrick
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Nazlamova, Liliya Angelova
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Wheway, Gabrielle
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Rose-Zerilli, Matthew
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West, Jonathan
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Pujato, Mario
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Chen, Xiaoting
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Woelk, Christopher H.
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MacArthur, Ben
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Ardern-Jones, Michael
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Friedmann, Peter S.
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Weirauch, Matthew T.
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Singh, Harinder
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Polak, Marta E.
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Sirvent Bernal, Sofia
c8c68bc8-a5a7-456d-899d-6e48ccfac02f
Vallejo Pulido, Andres
27bc0b94-0c40-4fd1-9533-7e267d588c0a
Davies, James
a93b4fc9-80a2-4620-ada6-c12f05c5ee38
Clayton, Kalum
499fec32-9297-45bd-9207-5ba699734844
Wu, Zhiguo
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Woo, Jeongmin
cd0ede17-cc62-43ca-acbc-4b235a5a53a2
Riddell, Jeremy
ad146967-c7ef-48be-9a84-c97ab39943e8
Chaudhri, Virendra K.
5e72e157-27f0-475e-bf8c-2183b54d7b8f
Stumpf, Patrick
dfdb286c-b321-46d3-8ba2-85b3b4a7f092
Nazlamova, Liliya Angelova
0cc21013-aeeb-4eef-af56-31f6fa0766fd
Wheway, Gabrielle
2e547e5d-b921-4243-a071-2208fd4cc090
Rose-Zerilli, Matthew
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West, Jonathan
f1c2e060-16c3-44c0-af70-242a1c58b968
Pujato, Mario
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Chen, Xiaoting
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Woelk, Christopher H.
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MacArthur, Ben
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Ardern-Jones, Michael
7ac43c24-94ab-4d19-ba69-afaa546bec90
Friedmann, Peter S.
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Weirauch, Matthew T.
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Singh, Harinder
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Polak, Marta E.
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Sirvent Bernal, Sofia, Vallejo Pulido, Andres, 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 and Polak, Marta E. (2020) Genomic programming of IRF4-expressing human Langerhans cells. Nature Communications, 11 (1), [313]. (doi:10.1038/s41467-019-14125-x).

Record type: Article

Abstract

Langerhans cells (LC) can prime tolerogenic as well as immunogenic responses in skin, but the genomic states and transcription factors (TFs) 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 program, 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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NCOMMS-19-03835B - Accepted Manuscript
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NCOMMS-19-03835B_supplementary - Accepted Manuscript
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More information

Accepted/In Press date: 19 December 2019
e-pub ahead of print date: 16 January 2020
Published date: 16 January 2020

Identifiers

Local EPrints ID: 437054
URI: http://eprints.soton.ac.uk/id/eprint/437054
ISSN: 2041-1723
PURE UUID: 7a5692f3-8adc-4419-93c4-644241023b62
ORCID for Sofia Sirvent Bernal: ORCID iD orcid.org/0000-0003-0050-8579
ORCID for Andres Vallejo Pulido: ORCID iD orcid.org/0000-0002-4688-0598
ORCID for Kalum Clayton: ORCID iD orcid.org/0000-0002-1143-3931
ORCID for Patrick Stumpf: ORCID iD orcid.org/0000-0003-0862-0290
ORCID for Gabrielle Wheway: ORCID iD orcid.org/0000-0002-0494-0783
ORCID for Matthew Rose-Zerilli: ORCID iD orcid.org/0000-0002-1064-5350
ORCID for Jonathan West: ORCID iD orcid.org/0000-0002-5709-6790

Catalogue record

Date deposited: 16 Jan 2020 17:30
Last modified: 26 Nov 2021 07:14

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Contributors

Author: Sofia Sirvent Bernal ORCID iD
Author: Andres Vallejo Pulido ORCID iD
Author: James Davies
Author: Kalum Clayton ORCID iD
Author: Zhiguo Wu
Author: Jeongmin Woo
Author: Jeremy Riddell
Author: Virendra K. Chaudhri
Author: Patrick Stumpf ORCID iD
Author: Liliya Angelova Nazlamova
Author: Jonathan West ORCID iD
Author: Mario Pujato
Author: Xiaoting Chen
Author: Christopher H. Woelk
Author: Ben MacArthur
Author: Peter S. Friedmann
Author: Matthew T. Weirauch
Author: Harinder Singh
Author: Marta E. Polak

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