IL-4 subverts mycobacterial containment in Mycobacterium tuberculosis-infected human macrophages

Protective immunity against Mycobacterium tuberculosis is poorly understood. The role of interleukin (IL)-4, the archetypal T-helper type 2 (Th2) cytokine, in the immunopathogenesis of human tuberculosis remains unclear. Blood and/or bronchoalveolar lavage fluid (BAL) were obtained from participants with pulmonary tuberculosis (TB) (n=23) and presumed latent TB infection (LTBI) (n=22). Messenger RNA expression levels of interferon (IFN)-gamma, IL-4 and its splice variant IL-4 delta 2 were determined by real-time PCR. The effect of human recombinant (hr) IL-4 on mycobacterial survival/containment (CFU.mL(-1)) 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-gamma ratio (p=0.01) was higher in TB versus LTBI. hrIL-4 reduced mycobacterial containment in infected macrophages (p<0.008) in a dose-dependent manner and was associated with an increase in Tregs (p<0.001), but decreased CD4(+)Th1 cytokine levels (CD4(+)IFN-gamma(+) p<0.001; CD4(+)TNF alpha(+) p=0.01). Blocking IL-4 significantly neutralised mycobacterial containment (p=0.03), CD4(+)IFN gamma(+) levels (p=0.03) and Treg expression (p=0.03). IL-4 can subvert mycobacterial containment in human macrophages, probably via perturbations in Treg and Th1-linked pathways. These data may have implications for the design of effective TB vaccines and host-directed therapies.