dc.contributor.author
Raftery, Martin J.
dc.contributor.author
Abdelaziz, Mohammed O.
dc.contributor.author
Hofmann, Jörg
dc.contributor.author
Schönrich, Günther
dc.date.accessioned
2019-04-01T11:16:15Z
dc.date.available
2019-04-01T11:16:15Z
dc.identifier.uri
https://refubium.fu-berlin.de/handle/fub188/24244
dc.identifier.uri
http://dx.doi.org/10.17169/refubium-2016
dc.description.abstract
Viruses often subvert antiviral immune responses by taking advantage of inhibitory immune signaling. We investigated if hantaviruses use this strategy. Hantaviruses cause viral hemorrhagic fever (VHF) which is associated with strong immune activation resulting in vigorous CD8+ T cell responses. Surprisingly, we observed that hantaviruses strongly upregulate PD-L1 and PD-L2, the ligands of checkpoint inhibitor programmed death-1 (PD-1). We detected high amounts of soluble PD-L1 (sPD-L1) and soluble PD-L2 (sPD-L2) in sera from hantavirus-infected patients. In addition, we observed hantavirus-induced PD-L1 upregulation in mice with a humanized immune system. The two major target cells of hantaviruses, endothelial cells and monocyte-derived dendritic cells, strongly increased PD-L1 and PD-L2 surface expression upon hantavirus infection in vitro. As an underlying mechanism, we found increased transcript levels whereas membrane trafficking of PD-L1 was not affected. Further analysis revealed that hantavirus-associated inflammatory signals and hantaviral nucleocapsid (N) protein enhance PD-L1 and PD-L2 expression. Cell numbers were strongly reduced when hantavirus-infected endothelial cells were mixed with T cells in the presence of an exogenous proliferation signal compared to uninfected cells. This is compatible with the concept that virus-induced PD-L1 and PD-L2 upregulation contributes to viral immune escape. Intriguingly, however, we observed hantavirus-induced CD8+ T cell bystander activation despite strongly upregulated PD-L1 and PD-L2. This result indicates that hantavirus-induced CD8+ T cell bystander activation bypasses checkpoint inhibition allowing an early antiviral immune response upon virus infection.
en
dc.rights.uri
https://creativecommons.org/licenses/by/4.0/
dc.subject
bystander activation
en
dc.subject
hantaviruses
en
dc.subject
viral immune evasion
en
dc.subject.ddc
600 Technik, Medizin, angewandte Wissenschaften::610 Medizin und Gesundheit::610 Medizin und Gesundheit
dc.title
Hantavirus-driven PD-L1/PD-L2 upregulation: An imperfect viral immune evasion mechanism
dc.type
Wissenschaftlicher Artikel
dcterms.bibliographicCitation.articlenumber
2560
dcterms.bibliographicCitation.doi
10.3389/fimmu.2018.02560
dcterms.bibliographicCitation.journaltitle
Frontiers in Immunology
dcterms.bibliographicCitation.originalpublishername
Frontiers Media S.A.
dcterms.bibliographicCitation.volume
9
refubium.affiliation
Charité - Universitätsmedizin Berlin
refubium.resourceType.isindependentpub
no
dcterms.accessRights.openaire
open access
dcterms.bibliographicCitation.pmid
30559738
dcterms.isPartOf.issn
1664-3224