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PLoS Pathog. 2019 Mar 14;15(3):e1007650. doi: 10.1371/journal.ppat.1007650. eCollection 2019 Mar.

Varicella zoster virus productively infects human peripheral blood mononuclear cells to modulate expression of immunoinhibitory proteins and blocking PD-L1 enhances virus-specific CD8+ T cell effector function.

Author information

1
Department of Neurology, University of Colorado School of Medicine, Aurora, Colorado, United States of America.
2
Department of Medicine, University of Washington, Seattle, Washington, United States of America.
3
Department of Medicine, Division of Allergy and Clinical Immunology, University of Colorado School of Medicine, Aurora, Colorado, United States of America.
4
Department of Laboratory Medicine, University of Washington, Seattle, Washington, United States of America.
5
Department of Global Health, University of Washington, Seattle, Washington, United States of America.
6
Vaccine and Infectious Disease Division, Fred Hutchinson Cancer Center, Seattle, Washington, United States of America.
7
Benaroya Research Institute, Seattle, Washington, United States of America.
8
Department of Ophthalmology, University of Colorado School of Medicine, Aurora, Colorado, United States of America.

Abstract

Varicella zoster virus (VZV) is a lymphotropic alpha-herpesvirinae subfamily member that produces varicella on primary infection and causes zoster, vascular disease and vision loss upon reactivation from latency. VZV-infected peripheral blood mononuclear cells (PBMCs) disseminate virus to distal organs to produce clinical disease. To assess immune evasion strategies elicited by VZV that may contribute to dissemination of infection, human PBMCs and VZV-specific CD8+ T cells (V-CD8+) were mock- or VZV-infected and analyzed for immunoinhibitory protein PD-1, PD-L1, PD-L2, CTLA-4, LAG-3 and TIM-3 expression using flow cytometry. All VZV-infected PBMCs (monocytes, NK, NKT, B cells, CD4+ and CD8+ T cells) and V-CD8+ showed significant elevations in PD-L1 expression compared to uninfected cells. VZV induced PD-L2 expression in B cells and V-CD8+. Only VZV-infected CD8+ T cells, NKT cells and V-CD8+ upregulated PD-1 expression, the immunoinhibitory receptor for PD-L1/PD-L2. VZV induced CTLA-4 expression only in V-CD8+ and no significant changes in LAG-3 or TIM-3 expression were observed in V-CD8+ or PBMC T cells. To test whether PD-L1, PD-L2 or CTLA-4 regulates V-CD8+ effector function, autologous PBMCs were VZV-infected and co-cultured with V-CD8+ cells in the presence of blocking antibodies against PD-L1, PD-L2 or CTLA-4; ELISAs revealed significant elevations in IFNγ only upon blocking of PD-L1. Together, these results identified additional immune cells that are permissive to VZV infection (monocytes, B cells and NKT cells); along with a novel mechanism for inhibiting CD8+ T cell effector function through induction of PD-L1 expression.

PMID:
30870532
PMCID:
PMC6435197
DOI:
10.1371/journal.ppat.1007650
[Indexed for MEDLINE]
Free PMC Article

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