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

BACKGROUND: Virus infections drive COPD exacerbations and progression. Anti-viral immunity centers on the activation of virus-specific CD8(+) T cells by viral epitopes presented on MHC class I molecules of infected cells. These epitopes are generated by the immunoproteasome, a specialized intracellular protein degradation machine, which is induced by anti-viral cytokines in infected cells. METHODS: We here analysed the effects of CS 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 CS-exposed Influenza A virus (IAV)-infected cells. Mass-spectrometry-based analysis of MHC class I-bound peptides uncovered the effects of CS on inflammatory antigen presentation in lung cells. IAV-specific CD8(+) T cell numbers were determined in peripheral patients' blood using tetramer-technology. RESULTS: CS impaired the induction of the immunoproteasome by cytokine signaling and viral infection in lung cells in vitro, ex vivo and in vivo. CS also altered the peptide repertoire of antigens presented on MHC class I under inflammatory conditions. Importantly, MHC class I-mediated activation of IAV-specific CD8(+) T cells was dampened by CS. 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.

• Chen, J.
• Wang, X.
• Schmalen, A.
• Haines, S.
• Wolff, M.
• Ma, H.
• Zhang, H.
• Stoleriu, M. G.
• Nowak, J.
• Nakayama, M.
• Bueno, M.
• Brands, J.
• Mora, A. L.
• Lee, J. S.
• Krauss-Etschmann, S.
• Dmitrieva, A.
• Frankenberger, M.
• Hofer, T. P.
• Noessner, E.
• Moosmann, A.
• Behr, J.
• Milger, K.
• Deeg, C. A.
• Staab-Weijnitz, C. A.
• Hauck, S. M.
• Adler, H.
• Goldmann, T.
• Gaede, K. I.
• Behrends, J.
• Kammerl, I. E.
• Meiners, S.