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Antiviral immunity centres on the activation of virus-specific CD8<jats:sup>+<\/jats:sup>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.<\/jats:p><\/jats:sec><jats:sec><jats:title>Methods<\/jats:title><jats:p>We analysed the effects of cigarette smoke on cytokine- and virus-mediated induction of the immunoproteasome<jats:italic>in vitro<\/jats:italic>,<jats:italic>ex vivo<\/jats:italic>and<jats:italic>in vivo<\/jats:italic>using RNA and Western blot analyses. CD8<jats:sup>+<\/jats:sup>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<jats:sup>+<\/jats:sup>T-cell numbers were determined in patients\u2019 peripheral blood using tetramer technology.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>Cigarette smoke impaired the induction of the immunoproteasome by cytokine signalling and viral infection in lung cells<jats:italic>in vitro<\/jats:italic>,<jats:italic>ex vivo<\/jats:italic>and<jats:italic>in vivo<\/jats:italic>. 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<jats:sup>+<\/jats:sup>T-cells was dampened by cigarette smoke. COPD patients exhibited reduced numbers of circulating IAV-specific CD8<jats:sup>+<\/jats:sup>T-cells compared to healthy controls and asthmatics.<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusion<\/jats:title><jats:p>Our data indicate that cigarette smoke interferes with MHC class I antigen generation and presentation and thereby contributes to impaired activation of CD8<jats:sup>+<\/jats:sup>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.<\/jats:p><\/jats:sec>","DOI":"10.1183\/13993003.01374-2022","type":"journal-article","created":{"date-parts":[[2023,6,29]],"date-time":"2023-06-29T11:55:14Z","timestamp":1688039714000},"page":"2201374","update-policy":"https:\/\/doi.org\/10.1183\/ers-crossmark-policy","source":"Crossref","is-referenced-by-count":39,"title":["Antiviral CD8<sup>+<\/sup>T-cell immune responses are impaired by cigarette smoke and in 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