title: RSV-induced bronchial epithelial cell PD-L1 expression inhibits CD8+ T cell nonspecific antiviral activity.
abstract: Respiratory syncytial virus (RSV) is a major cause of bronchiolitis in infants. It is also responsible for high morbidity and mortality in the elderly. Programmed death ligands (PD-Ls) on antigen-presenting cells interact with receptors on T cells to regulate immune responses. The programmed death receptor-ligand 1/programmed death receptor 1 (PD-L1-PD-1) pathway is inhibitory in chronic viral infections, but its role in acute viral infections is unclear. We hypothesized that bronchial epithelial cell (BEC) expression of PD-Ls would inhibit local effector CD8(+) T cell function. We report that RSV infection of primary human BECs strongly induces PD-L1 expression. In a co-culture system of BECs with purified CD8(+) T cells, we demonstrated that RSV-infected BECs increased CD8(+) T cell activation, proliferation, and antiviral function. Blocking PD-L1 on RSV-infected BECs co-cultured with CD8(+) T cells enhanced CD8(+) T cell IFN-γ, IL-2, and granzyme B production. It also decreased the virus load of the BECs. Based on our findings, we believe therapeutic strategies that target the PD-L1-PD-1 pathway might increase antiviral immune responses to RSV and other acute virus infections.
authors.affiliation: Department of Respiratory Medicine, National Heart and Lung Institute, MRC and Asthma UK Centre in Allergic Mechanisms of Asthma and Centre for Respiratory Infection, Imperial College London, Norfolk Place, London, United Kingdom.
authors.forename: Aurica G
authors.initials: AG
authors.lastname: Telcian
authors.forename: Vasile
authors.initials: V
authors.lastname: Laza-Stanca
authors.forename: Michael R
authors.initials: MR
authors.lastname: Edwards
authors.forename: James A
authors.initials: JA
authors.lastname: Harker
authors.forename: Hongwei
authors.initials: H
authors.lastname: Wang
authors.forename: Nathan W
authors.initials: NW
authors.lastname: Bartlett
authors.forename: Patrick
authors.initials: P
authors.lastname: Mallia
authors.forename: Mihnea T
authors.initials: MT
authors.lastname: Zdrenghea
authors.forename: Tatiana
authors.initials: T
authors.lastname: Kebadze
authors.forename: Anthony J
authors.initials: AJ
authors.lastname: Coyle
authors.forename: Peter J M
authors.initials: PJ
authors.lastname: Openshaw
authors.forename: Luminita A
authors.initials: LA
authors.lastname: Stanciu
authors.forename: Sebastian L
authors.initials: SL
authors.lastname: Johnston
mesh_terms: D015703:Antigens, CD / Q000096:biosynthesis*; D017209:Apoptosis; D060890:B7-H1 Antigen; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology*; D002478:Cells, Cultured; D018920:Coculture Techniques; D004847:Epithelial Cells / Q000821:virology*; D006801:Humans; D007108:Immune Tolerance; D012136:Respiratory Syncytial Viruses / Q000276:immunology* / Q000472:pathogenicity*
chemical_list: D015703:Antigens, CD; D060890:B7-H1 Antigen; C423236:CD274 protein, human