Viral infection of human lung macrophages increases PDL1 expression via IFNβ
Viral infection of human lung macrophages increases PDL1 expression via IFNβ
Lung macrophages are an important defence against respiratory viral infection and recent work has demonstrated that influenza-induced macrophage PDL1 expression in the murine lung leads to rapid modulation of CD8+ T cell responses via the PD1 receptor. This PD1/PDL1 pathway may downregulate acute inflammatory responses to prevent tissue damage. The aim of this study was to investigate the mechanisms of PDL1 regulation by human macrophages in response to viral infection. Ex-vivo viral infection models using influenza and RSV were established in human lung explants, isolated lung macrophages and monocyte-derived macrophages (MDM) and analysed by flow cytometry and RT-PCR. Incubation of lung explants, lung macrophages and MDM with X31 resulted in mean cellular infection rates of 18%, 18% and 29% respectively. Viral infection significantly increased cell surface expression of PDL1 on explant macrophages, lung macrophages and MDM but not explant epithelial cells. Infected MDM induced IFN? release from autologous CD8+ T cells, an effect enhanced by PDL1 blockade. We observed increases in PDL1 mRNA and IFN? mRNA and protein release by MDM in response to influenza infection. Knockdown of IFN? by siRNA, resulted in a 37.5% reduction in IFN? gene expression in response to infection, and a significant decrease in PDL1 mRNA. Furthermore, when MDM were incubated with IFN?, this cytokine caused increased expression of PDL1 mRNA. These data indicate that human macrophage PDL1 expression modulates CD8+ cell IFN? release in response to virus and that this expression is regulated by autologous IFN? production.
1-16
Staples, Karl J.
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Nicholas, Ben
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McKendry, Richard T.
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Spalluto, C. Mirella
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Wallington, Joshua C.
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Bragg, Craig W.
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Robinson, Emily C.
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Martin, Kirstin
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Djukanović, Ratko
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Wilkinson, Tom M.A.
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16 March 2015
Staples, Karl J.
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Nicholas, Ben
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McKendry, Richard T.
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Spalluto, C. Mirella
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Wallington, Joshua C.
bbbcfb18-8d5c-4ce3-9917-a963baedf422
Bragg, Craig W.
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Robinson, Emily C.
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Martin, Kirstin
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Djukanović, Ratko
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Wilkinson, Tom M.A.
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Staples, Karl J., Nicholas, Ben, McKendry, Richard T., Spalluto, C. Mirella, Wallington, Joshua C., Bragg, Craig W., Robinson, Emily C., Martin, Kirstin, Djukanović, Ratko and Wilkinson, Tom M.A.
(2015)
Viral infection of human lung macrophages increases PDL1 expression via IFNβ.
PLoS ONE, 10 (3), .
(doi:10.1371/journal.pone.0121527).
(PMID:25775126)
Abstract
Lung macrophages are an important defence against respiratory viral infection and recent work has demonstrated that influenza-induced macrophage PDL1 expression in the murine lung leads to rapid modulation of CD8+ T cell responses via the PD1 receptor. This PD1/PDL1 pathway may downregulate acute inflammatory responses to prevent tissue damage. The aim of this study was to investigate the mechanisms of PDL1 regulation by human macrophages in response to viral infection. Ex-vivo viral infection models using influenza and RSV were established in human lung explants, isolated lung macrophages and monocyte-derived macrophages (MDM) and analysed by flow cytometry and RT-PCR. Incubation of lung explants, lung macrophages and MDM with X31 resulted in mean cellular infection rates of 18%, 18% and 29% respectively. Viral infection significantly increased cell surface expression of PDL1 on explant macrophages, lung macrophages and MDM but not explant epithelial cells. Infected MDM induced IFN? release from autologous CD8+ T cells, an effect enhanced by PDL1 blockade. We observed increases in PDL1 mRNA and IFN? mRNA and protein release by MDM in response to influenza infection. Knockdown of IFN? by siRNA, resulted in a 37.5% reduction in IFN? gene expression in response to infection, and a significant decrease in PDL1 mRNA. Furthermore, when MDM were incubated with IFN?, this cytokine caused increased expression of PDL1 mRNA. These data indicate that human macrophage PDL1 expression modulates CD8+ cell IFN? release in response to virus and that this expression is regulated by autologous IFN? production.
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Accepted/In Press date: 3 February 2015
Published date: 16 March 2015
Organisations:
Faculty of Medicine
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Local EPrints ID: 375589
URI: http://eprints.soton.ac.uk/id/eprint/375589
ISSN: 1932-6203
PURE UUID: ceffd005-6d20-4d96-971a-5945d4a0b1ab
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Date deposited: 30 Mar 2015 11:28
Last modified: 15 Mar 2024 03:27
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Author:
Ben Nicholas
Author:
Richard T. McKendry
Author:
C. Mirella Spalluto
Author:
Joshua C. Wallington
Author:
Craig W. Bragg
Author:
Emily C. Robinson
Author:
Kirstin Martin
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