RT Journal Article SR Electronic T1 IL-4 subverts mycobacterial containment in Mycobacterium tuberculosis-infected human macrophages JF European Respiratory Journal JO Eur Respir J FD European Respiratory Society SP 1802242 DO 10.1183/13993003.02242-2018 VO 54 IS 2 A1 Anil Pooran A1 Malika Davids A1 Andrew Nel A1 Aubrey Shoko A1 Jonathan Blackburn A1 Keertan Dheda YR 2019 UL http://erj.ersjournals.com/content/54/2/1802242.abstract AB 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)-γ, IL-4 and its splice variant IL-4δ2 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-γ 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-γ+ p<0.001; CD4+TNFα+ p=0.01). Blocking IL-4 significantly neutralised mycobacterial containment (p=0.03), CD4+IFNγ+ 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.TB patients express high IL-4 levels and exhibit a compartment-specific skewed Th2/Th1 response. In vitro, IL-4 subverts mycobacterial containment in M. tuberculosis-infected human macrophages indicating its potential utility as an immunotherapeutic target. bit.ly/2HclAOH