Viral infection of human lung macrophages increases PDL1 expression via IFNβ.

Karl J Staples,Tom M A Wilkinson,Ratko Djukanović,C Mirella Spalluto,Ben Nicholas,Richard T Mckendry,Kirstin Martin,Craig W Bragg,Emily C Robinson,Joshua C Wallington,Dennis W Metzger

doi:10.1371/journal.pone.0121527

Karl J Staples, Tom M A Wilkinson + Show 9 more

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https://doi.org/10.1371/journal.pone.0121527

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Journal: PloS one	Publication Date: Mar 16, 2015
Citations: 74	License type: CC BY 4.0

Affiliation: Southampton General Hospital

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 IFNγ release from autologous CD8+ T cells, an effect enhanced by PDL1 blockade. We observed increases in PDL1 mRNA and IFNβ mRNA and protein release by MDM in response to influenza infection. Knockdown of IFNβ by siRNA, resulted in a 37.5% reduction in IFNβ gene expression in response to infection, and a significant decrease in PDL1 mRNA. Furthermore, when MDM were incubated with IFNβ, this cytokine caused increased expression of PDL1 mRNA. These data indicate that human macrophage PDL1 expression modulates CD8+ cell IFNγ release in response to virus and that this expression is regulated by autologous IFNβ production.

Highlights

The optimal immune response to respiratory viral infections requires a coordinated and balanced response from an array of innate and adaptive responses
Since type I IFN expression was observed in response to influenza infection and previous studies have suggested that these cytokines could induce PDL1 expression[18,19], we investigated whether rhIFNβ could induce PDL1 gene expression in our monocytederived macrophages (MDM) model (Fig. 7A)
We have demonstrated for the first time that in the acute phase of influenza infection macrophages are the primary cells in the human lung expressing PDL1

Summary

Introduction

The optimal immune response to respiratory viral infections requires a coordinated and balanced response from an array of innate and adaptive responses. The influenza virus primarily infects the respiratory epithelium, this virus can infect and replicate in human alveolar macrophages[1,2,3]. Macrophages are a key line of defence in the respiratory. RD and TMAW have applied for a patent for the explant infection model (PCT/GB2010/050821 "Ex Vivo Modelling of Therapeutic Interventions"). RD is a co-founder and holds shares in Synairgen Plc. RD is a co-founder and holds shares in Synairgen Plc These interests do not alter the authors' adherence to PLOS ONE policies on sharing data and materials. The remaining authors declare no conflict of interest

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