title: Continuous and discontinuous cigarette smoke exposure differentially affects protective Th1 immunity against pulmonary tuberculosis.
abstract: Pulmonary tuberculosis (TB), caused by Mycobacterium tuberculosis, is the leading cause of death due to a bacterial pathogen. Emerging epidemiologic evidence suggests that the leading risk factor associated with TB mortality is cigarette smoke exposure. Despite this, it remains poorly understood what is the effect of cigarette smoke exposure on anti-TB immunity and whether its potential detrimental effect can be reversed by cigarette smoking cessation. In our current study, we have investigated the impact of both continuous and discontinuous cigarette smoke exposure on the development of anti-mycobacterial type 1 immunity in murine models. We find that while continuous cigarette smoke exposure severely impairs type 1 immunity in the lung, a short-term smoking cessation allows rapid restoration of anti-mycobacterial immunity. The ability of continuous cigarette smoke exposure to dampen type 1 protective immunity is attributed locally to its affects on innate immune cells in the lung. Continuous cigarette smoke exposure locally, by not systemically, impairs APC accumulation and their production of TNF, IL-12, and RANTES, blunts the recruitment of CD4+IFN-γ+ T cells to the lung, and weakens the formation of granuloma. On the other hand, smoking cessation was found to help restore type 1 immunity by rapidly improving the functionality of lung APCs, enhancing the recruitment of CD4+IFN-γ+ T cells to the lung, and promoting the formation of granuloma. Our study for the first time demonstrates that continuous, but not discontinuous, cigarette smoke exposure severely impedes the lung expression of anti-TB Th1 immunity via inhibiting innate immune activation and lung T cell recruitment. Our findings thus suggest cigarette smoking cessation to be beneficial to the control of pulmonary TB.
authors.affiliation: McMaster Immunology Research Centre, and Department of Pathology & Molecular Medicine, McMaster University, Hamilton, Ontario, Canada.
authors.forename: Christopher R
authors.initials: CR
authors.lastname: Shaler
authors.forename: Carly N
authors.initials: CN
authors.lastname: Horvath
authors.forename: Sarah
authors.initials: S
authors.lastname: McCormick
authors.forename: Mangalakumari
authors.initials: M
authors.lastname: Jeyanathan
authors.forename: Amandeep
authors.initials: A
authors.lastname: Khera
authors.forename: Anna
authors.initials: A
authors.lastname: Zganiacz
authors.forename: Joanna
authors.initials: J
authors.lastname: Kasinska
authors.forename: Martin R
authors.initials: MR
authors.lastname: Stampfli
authors.forename: Zhou
authors.initials: Z
authors.lastname: Xing
mesh_terms: D000818:Animals; D000938:Antigen-Presenting Cells / Q000276:immunology*; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology; D004797:Enzyme-Linked Immunosorbent Assay; D005260:Female; D007111:Immunity, Cellular / Q000187:drug effects*; D008168:Lung / Q000382:microbiology / Q000473:pathology; D051379:Mice; D008810:Mice, Inbred C57BL; D009569:Nitric Oxide / Q000378:metabolism; D012907:Smoking / Q000009:adverse effects*; D016540:Smoking Cessation; D018417:Th1 Cells / Q000187:drug effects* / Q000276:immunology; D014397:Tuberculosis, Pulmonary / Q000276:immunology*
chemical_list: D009569:Nitric Oxide