IL-4 subverts mycobacterial containment inMycobacterium tuberculosis-infected human macrophages

Abstract

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.

Host‐directed therapy to combat mycobacterial infections*

“…133,134 In several patients suffering from pulmonary TB, direct administration of IFNγ accelerated sputum-smear conversion and improved chest radiograph. 135,136 131 Blocking IL-4 completely alleviated these effects and improved bacterial control, 131 suggesting Th skewing could be an interesting target for HDT.…”

“…Th1‐responses, characterized by high IFN‐γ secretion, are crucial in effective anti‐ Mtb immune responses 130‐132 . Nevertheless, Mav and Mtb reduce cellular responses to IFN‐γ and deficiencies in the IL‐12/IL‐23/IFN‐γ‐axis increase susceptibility to Mav infections 133,134 .…”

“…Th2‐responses have been associated with active cavitary TB disease or TB treatment failure, 130,131 and administration of IL‐4, a hallmark Th2‐cytokine, impaired mycobacterial control by human macrophages and enhanced the proportion of regulatory T‐cells in vitro 131 . Blocking IL‐4 completely alleviated these effects and improved bacterial control, 131 suggesting Th skewing could be an interesting target for HDT.…”

“…Modulating T‐cell responses to restore immunity can be mediated by vaccination or T‐cell cytokine therapies. Administration of IL‐12 141 or IL‐24 142 or blocking Th2 cytokine IL‐4, 131 promotes Th1 responses with lasting IFN‐γ production that may be preferred over IFN‐γ administration. Which of these strategies is (most) efficacious and which patients benefit most from this therapy remains to be addressed.…”

“…145Th2-responses have been associated with active cavitary TB disease or TB treatment failure,130,131 and administration of IL-4, a hallmark…”