Viral dsRNA drives hyperinflammatory but blunted antiviral responses with enhanced PD-L1 induction in a COPD-like airway epithelial model

Programmed death-ligand 1 (PD-L1) suppresses T-cell activation during antiviral immune responses, and its expression is increased in airway epithelial cells after viral infection. Because chronic obstructive pulmonary disease (COPD) is characterized by excessive airway inflammation and frequent virus-triggered exacerbations, we investigated the regulation and possible functional relevance of PD-L1 in a COPD-like airway epithelial model in response to viral double-stranded ribonucleic acid (dsRNA) stimulation. Human bronchial epithelial 16HBE14o-cells and β/γ epithelial sodium channel (ENaC)-overexpressing 16HBE14o- (β/γENaC-16HBE14o-) cells were stimulated with polyinosinic:polycytidylic acid [poly(I:C)]. In β/γENaC-16HBE14o-cells, poly(I:C) markedly enhanced the expression of pro-inflammatory mediators, including Toll-like receptor 3 (TLR3), interleukin-6 (IL-6), and tumor necrosis factor-α (TNF-α), along with increased p38 phosphorylation and nuclear accumulation of nuclear factor kappa B (NF-κB) subunits. In contrast, antiviral signaling was attenuated, as shown by reduced interferon regulatory factor 3 (IRF3) phosphorylation and weaker interferon-β (IFN-β) induction compared with parental cells. Notably, poly(I:C)-induced PD-L1 expression was significantly higher in β/γENaC-16HBE14o-cells than in normal airway epithelial cells. Pharmacological inhibition experiments showed that PD-L1 induction depended on p38 signaling rather than NF-κB. In a co-culture system, blockade of programmed cell death-1 (PD-1)/PD-L1 interaction with BMS202 tended to increase IL-2 production by Jurkat T cells exposed to poly(I:C)-stimulated β/γENaC-16HBE14o-cells, with a large effect size. These findings suggest that COPD-like airway epithelial cells display exaggerated inflammatory responses but impaired antiviral responses to viral dsRNA, accompanied by enhanced p38-dependent PD-L1 induction, which may contribute to reduced T-cell activation during COPD exacerbation.