Antiviral CD8+ T-cell immune responses are impaired by cigarette smoke and in COPD

Graphical abstract Main findings of the study. Cigarette smoke impairs virus-induced upregulation of the major histocompatibility complex (MHC) class I antigen presentation machinery resulting in reduced activation of antiviral CD8+ T-cells. 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 in vitro, ex vivo and in vivo 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 in vitro, ex vivo and in vivo. 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. Extract COPD is characterised by progressive airflow limitation and alveolar destruction, resulting in reduced lung function and severely diminished quality of life [1]. >10% of the world's population are diagnosed with COPD, with a mortality that makes COPD the third leading cause of death globally [2]. Tobacco smoke consumption is one of the main risk factors for developing COPD [1]. Exacerbations of the disease with sudden decline in lung function are related to viral infections such as rhinovirus and influenza A virus (IAV) or bacteria [3, 4] and contribute to COPD progression [5, 6]. Tweetable abstract Cigarette smoke impairs virus-induced upregulation of the MHC class I antigen presentation machinery resulting in reduced activation of antiviral CD8+ T-cells. This may reduce viral clearance and increase susceptibility to viral exacerbations in COPD. https://bit.ly/43o0p3D