title: Dysregulation of Antiviral Function of CD8(+) T Cells in the Chronic Obstructive Pulmonary Disease Lung. Role of the PD-1-PD-L1 Axis.
abstract: BACKGROUND
  Patients with chronic obstructive pulmonary disease (COPD) are susceptible to respiratory viral infections that cause exacerbations. The mechanisms underlying this susceptibility are not understood. Effectors of the adaptive immune response-CD8(+) T cells that clear viral infections-are present in increased numbers in the lungs of patients with COPD, but they fail to protect against infection and may contribute to the immunopathology of the disease.
  
  
  OBJECTIVE
  CD8(+) function and signaling through the programmed cell death protein (PD)-1 exhaustion pathway were investigated as a potential key mechanism of viral exacerbation of the COPD lung.
  
  
  METHODS
  Tissue from control subjects and patients with COPD undergoing lung resection was infected with live influenza virus ex vivo. Viral infection and expression of lung cell markers were analyzed using flow cytometry.
  
  
  RESULTS
  The proportion of lung CD8(+) T cells expressing PD-1 was greater in COPD (mean, 16.2%) than in controls (4.4%, P = 0.029). Only epithelial cells and macrophages were infected with influenza, and there was no difference in the proportion of infected cells between controls and COPD. Infection up-regulated T-cell PD-1 expression in control and COPD samples. Concurrently, influenza significantly up-regulated the marker of cytotoxic degranulation (CD107a) on CD8(+) T cells (P = 0.03) from control subjects but not on those from patients with COPD. Virus-induced expression of the ligand PD-L1 was decreased on COPD macrophages (P = 0.04) with a corresponding increase in IFN-γ release from infected COPD explants compared with controls (P = 0.04).
  
  
  CONCLUSIONS
  This study has established a signal of cytotoxic immune dysfunction and aberrant immune regulation in the COPD lung that may explain both the susceptibility to viral infection and the excessive inflammation associated with exacerbations.
authors.affiliation: 1 University of Southampton Faculty of Medicine, Sir Henry Wellcome Laboratories, and.
authors.forename: Richard T
authors.initials: RT
authors.lastname: McKendry
authors.affiliation: 1 University of Southampton Faculty of Medicine, Sir Henry Wellcome Laboratories, and.
authors.forename: C Mirella
authors.initials: CM
authors.lastname: Spalluto
authors.affiliation: 1 University of Southampton Faculty of Medicine, Sir Henry Wellcome Laboratories, and.
authors.forename: Hannah
authors.initials: H
authors.lastname: Burke
authors.affiliation: 1 University of Southampton Faculty of Medicine, Sir Henry Wellcome Laboratories, and.
authors.forename: Ben
authors.initials: B
authors.lastname: Nicholas
authors.affiliation: 1 University of Southampton Faculty of Medicine, Sir Henry Wellcome Laboratories, and.
authors.forename: Doriana
authors.initials: D
authors.lastname: Cellura
authors.affiliation: 1 University of Southampton Faculty of Medicine, Sir Henry Wellcome Laboratories, and.
authors.forename: Aymen
authors.initials: A
authors.lastname: Al-Shamkhani
authors.affiliation: 1 University of Southampton Faculty of Medicine, Sir Henry Wellcome Laboratories, and.
authors.forename: Karl J
authors.initials: KJ
authors.lastname: Staples
authors.affiliation: 1 University of Southampton Faculty of Medicine, Sir Henry Wellcome Laboratories, and.|2 Southampton National Institute for Health Research Respiratory Biomedical Research Unit, Southampton General Hospital, Southampton, United Kingdom.
authors.forename: Tom M A
authors.initials: TM
authors.lastname: Wilkinson
mesh_terms: D000368:Aged; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology*; D005260:Female; D005434:Flow Cytometry; D006801:Humans; D007251:Influenza, Human / Q000150:complications / Q000276:immunology*; D008168:Lung / Q000276:immunology*; D008297:Male; D008875:Middle Aged; D061026:Programmed Cell Death 1 Receptor / Q000276:immunology*; D029424:Pulmonary Disease, Chronic Obstructive / Q000150:complications / Q000276:immunology*; D015398:Signal Transduction / Q000276:immunology; D015854:Up-Regulation / Q000276:immunology
chemical_list: C105992:PDCD1 protein, human; D061026:Programmed Cell Death 1 Receptor
keywords: PD-1; T cell; chronic obstructive pulmonary disease; macrophage; viral infection