BACKGROUND

Virus infections drive COPD exacerbations and progression. Antiviral immunity centres 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 specialised intracellular protein degradation machine, which is induced by antiviral cytokines in infected cells.

METHODS

We analysed the effects of cigarette smoke on cytokine- and virus-mediated induction of the immunoproteasome , and using RNA and Western blot analyses. CD8 T-cell activation was determined in co-culture assays with cigarette smoke-exposed influenza A virus (IAV)-infected cells. Mass-spectrometry-based analysis of MHC class I-bound peptides uncovered the effects of cigarette smoke on inflammatory antigen presentation in lung cells. IAV-specific CD8 T-cell numbers were determined in patients' peripheral blood using tetramer technology.

RESULTS

Cigarette smoke impaired the induction of the immunoproteasome by cytokine signalling and viral infection in lung cells , and . In addition, cigarette smoke altered the peptide repertoire of antigens presented on MHC class I molecules under inflammatory conditions. Importantly, MHC class I-mediated activation of IAV-specific CD8 T-cells was dampened by cigarette smoke. COPD patients exhibited reduced numbers of circulating IAV-specific CD8 T-cells compared to healthy controls and asthmatics.

CONCLUSION

Our data indicate that cigarette smoke interferes with MHC class I antigen generation and presentation and thereby contributes to impaired activation of CD8 T-cells upon virus infection. This adds important mechanistic insight on how cigarette smoke mediates increased susceptibility of smokers and COPD patients to viral infections.