IL-4 subverts mycobacterial containment in M. tuberculosis-infected human macrophages

198/200) Protective immunity against Mycobacterium tuberculosis is poorly understood. The role of interleukin-4 (IL-4), the archetypal T-helper-2 (Th2) cytokine, in the immunopathogenesis of human tuberculosis remains unclear. Blood and/or broncho-alveolar lavage fluid (BAL) were obtained from participants with pulmonary TB (TB; n=23) and presumed latent TB infection (LTBI; n=22). Messenger RNA expression levels of interferon-gamma (IFN-γ), IL-4, and its splice variant IL-4δ2 were determined by real-time PCR. The effect of human recombinant IL-4 (hrIL-4) on mycobacterial survival/ containment [colony-forming-units (CFU/ml] was evaluated in M. tuberculosis-infected macrophages co-cultured with mycobacterial antigen-primed effector T-cells. Regulatory T-cell (Treg) and Th1 cytokine levels were evaluated using flow cytometry. In blood, but not BAL, IL-4 mRNA levels (p=0.02) and the IL-4/IFN-γ ratio (p=0.01) was higher in TB versus LTBI. hrIL-4 reduced mycobacterial containment in infected macrophages (p<0.008) in a dosedependent manner and was associated with an increase in Tregs (p<0.001) but decreased CD4Th1 cytokine levels (CD4IFN-γ: p<0.001; CD4TNFα: p=0.01). Blocking IL-4 significantly neutralized mycobacterial containment (p=0.03), CD4IFNγ levels (p=0.03) and Treg expression (p=0.03). IL-4 can subvert mycobacterial containment in human macrophages, likely via perturbations in Treg and Th1-linked pathways. These data may have implications in the design of effective TB vaccines and hostdirected therapies.