Dysregulation of Antiviral Function of CD8⁺T Cells in the Chronic Obstructive Pulmonary Disease Lung. Role of the PD-1–PD-L1 Axis

Abstract

Rationale: 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 1 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. Objectives: CD81 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. Measurements and Main Results:The proportion of lung CD8 1 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 CD81 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-g 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.

Influenza vaccination for patients with chronic obstructive pulmonary disease: understanding immunogenicity, efficacy and effectiveness

“…As an important regulator of T-lymphocyte function which is associated with a loss of cytotoxic function, the upregulation of PD-1 in T lymphocytes reduces CD8+ T-cell function in response to influenza. Specifically, this was associated with diminished T-cell cytotoxic degranulation in response to viral infection, supporting the concept of diminished T-lymphocyte response to viral infection in patients with COPD [McKendry et al 2015].…”

Reply: The PD-1–PD-L1 Axis in Chronic Obstructive Pulmonary Disease

“…We thank Dr Stoll and colleagues for highlighting the clinically important issues raised by the recent work on the PD1 axis in COPD (1,2). In light of these findings we share their concern that the use of anti-PD-1-PD-L1 therapies in patients with non-small cell lung cancer (NSCLC) and COPD may have unwanted effects on the underlying airway inflammatory process.…”

Urban particulate matter stimulation of human dendritic cells enhances priming of naive CD8 T lymphocytes

“…recently showed that upon ex vivo infection of resected lung tissue with influenza A virus, there was significantly greater IFN‐ γ production by explants from patients with COPD than from healthy controls,49 suggesting that inadequate IFN‐ γ production is not the cause of pathological inflammation in viral infections in patients with COPD 49…”