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 non-smokers, smokers and ex-smokers, after infection with Mycobacterium tuberculosis (Mtb).

Methods: AM were acquired at bronchoscopy, number and viability from smoking donors were compared to non-smoking donors. AM were challenged in vitro with Mtb and intracellular bacterial viability was measured. Cytokine secretion was measured 24hrs post-infection by ELISA. Previously we determined the frequency of CD4+FoxP3+ T cells in the presence or absence of allogeneic AM, data was reanalysed to separate the patient subjects according to smoking status.

Measurements and Main Results: There were significantly more AM from smokers compared to non-smokers or ex-smokers (p<0.01). AM from smokers could not control intracellular Mtb growth. Non-smokers' AM generated significantly more TNF-α, IFN-γ and IL-1β following Mtb infection compared to uninfected (p<0.05). However Mtb-infected AM from smokers did not secrete significantly more TNF-α, IFN-γ and IL-1β compared to uninfected smokers' AM. AM taken from ex-smokers also failed to secrete significantly increased TNF-α, IFN-γ and IL-1β after Mtb infection. Both smokers' and non-smokers' AM induced FoxP3+ T regulatory (Treg) 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 which provide some mechanistic explanations whereby cigarette smoking renders a patient susceptible to tuberculosis infection and disease.