Abstract
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−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, likely via perturbations in Treg and Th1-linked pathways. These data may have implications in the design of effective TB vaccines and host-directed therapies.
Footnotes
This manuscript has recently been accepted for publication in the European Respiratory Journal. It is published here in its accepted form prior to copyediting and typesetting by our production team. After these production processes are complete and the authors have approved the resulting proofs, the article will move to the latest issue of the ERJ online. Please open or download the PDF to view this article.
Conflict of interest: Dr. Pooran has nothing to disclose.
Conflict of interest: Dr. Davids has nothing to disclose.
Conflict of interest: Dr. Nel has nothing to disclose.
Conflict of interest: Dr. Shoko has nothing to disclose.
Conflict of interest: Dr. Blackburn has nothing to disclose.
Conflict of interest: Dr. Dheda has nothing to disclose.
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