Cigarette Smoking Impairs Human Pulmonary Immunity to Mycobacterium tuberculosis

Rationale: Cigarette smoking is linked to important aspects of tuberculosis, such as susceptibility to infection, disease reactivation, mortality, transmission, and persistent infectiousness. The mechanistic basis for this remains poorly understood. Objectives: To compare the functional impairment seen in human alveolar macrophages (AM) from nonsmokers, smokers, and ex-smokers after infection with Mycobacterium tuberculosis (Mtb). Methods: AM were acquired at bronchoscopy, and number and viability from smoking donors were compared with nonsmoking donors. AM were challenged in vitro with Mtb and intracellular bacterial viability was measured. Cytokine secretion was measured 24 hours postinfection by ELISA. Previously we determined the frequency of CD4(+)FoxP3(+) T cells in the presence or absence of allogeneic AM, and data were reanalyzed to separate the patient subjects according to smoking status. Measurements and Main Results: There were significantly more AM from smokers compared With nonsmokers or ex-smokers (P < 0.01). AM from smokers could not control intracellular Mtb growth. Nonsmokers' AM generated significantly More tumor necrosis factor (TNF)-alpha, IFN-gamma, and IL-1 beta after Mtb infection compared with uninfected AM (P < 0.05). However, Mtb-infected AM from smokers did not secrete significantly more TNF-alpha, IFN-gamma, and IL-1 beta compared with uninfected smokers' AM. AM taken from ex-smokers also failed to secrete significantly increased TNF-alpha, IFN-gamma, and IL-1 beta after Mtb infection. Both smokers' and nonsmokers' AM induced FoxP3(+) T regulatory cell phenotype responses in allogeneic admixed T cells (>4.8 fold; P < 0.05): Even after Mtb infection, AM continued to drive this regulatory phenotype. Conclusions: In smokers, the pulmonary compartment has a number of macrophage-specific immune impairments that provide some mechanistic explanations Whereby cigarette smoking, renders a patient susceptible to tuberculosis infection and disease.