Virus infections drive COPD exacerbations and contribute to COPD progression. Cigarette smoke dampens anti-viral immunity, which possibly contributes to defective responses to viral infections in COPD patients. Anti-viral immunity centers on the activation of virus-specific CD8+ T cells by viral epitopes presented on major histocompatibility complex (MHC) class I molecules of infected cells. These epitopes are generated by the immunoproteasome, a specialized type of proteasome, that is upregulated by interferons upon infection. The effect of cigarette smoke on induction of the immunoproteasome and MHC class I-mediated CD8+ T cell activation is unresolved.

We here demonstrate that cigarette smoke attenuates cytokine and virus-induced upregulation of the immunoproteasome in vitro, ex vivo and in vivo. Using a CD8+ T cell activation assay, we show diminished MHC class I-mediated activation of influenza A virus (IAV)-specific CD8+ T cells by cigarette smoke extract. Moreover, cigarette smoke profoundly altered the repertoire of inflammatory MHC class I antigens in lung epithelial cells as revealed by advanced mass-spectrometry-based immunopeptidome analysis. Of note, COPD patients have reduced numbers of circulating IAV-specific CD8+ T cells compared to healthy controls and asthmatics.

In conclusion, cigarette smoke causes defective immunoproteasome activation and MHC I antigen presentation in lung cells that results in impaired activation of CD8+ T cells upon virus infection. This may contribute to reduced viral clearance and increased susceptibility to viral exacerbations in COPD.