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• W4200059543 abstract "Abstract The prevailing model of protective immunity to tuberculosis is that CD4 T cells produce the cytokine IFN-γ to activate bactericidal mechanisms in infected macrophages. Recent evidence has expanded this model, and it is now clear that CD4 T cells can control M. tuberculosis infection in the absence of IFN-γ production. To identify factors and pathways involved in IFN-γ-independent control, we developed a co-culture model using CD4 T cells isolated from the lungs of infected mice and M. tuberculosis-infected murine bone marrow-derived macrophages (BMDMs). We show that IFN-γ-independent control is primarily mediated by CD4 T cell production of the cytokine GM-CSF and requires activation of the macrophage transcription factor HIF-1α. HIF-1α activation drives a metabolic shift toward aerobic glycolysis and leads to the production of lipid droplets, both of which support host defense against infection. Surprisingly, recombinant GM-CSF is insufficient to rescue the absence of control by GM-CSF-deficient CD4 T cells during co-culture with BMDMs. In peritoneal macrophages, GM-CSF is sufficient to control growth, induces lipid droplet biogenesis, and requires HIF-1α expression for control. While HIF-1α-mediated control following IFN-γ stimulation requires nitric oxide, we find that HIF-1α activation by CD4 T cells and recombinant GM-CSF is nitric oxide-independent, implying a distinct pathway of activation. In addition to GM-CSF, CD4 T cells produce a factor that helps maintain phagosome membrane integrity during infection and blocks bacterial access to host lipids, a primary nutrient source. These results advance our understanding of CD4 T cell-mediated immunity to M. tuberculosis , clarify the role of nitric oxide as primarily immunomodulatory during M. tuberculosis infection, and reveal a novel mechanism for the activation of HIF-1α. Furthermore, we establish a previously unknown functional link between GM-CSF and HIF-1α and provide evidence that CD4 T cell-derived GM-CSF is a potent bactericidal effector." @default.
• W4200059543 created "2021-12-31" @default.
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• W4200059543 date "2021-12-16" @default.
• W4200059543 modified "2023-10-14" @default.
• W4200059543 title "IFN-γ-independent control of<i>M. tuberculosis</i>requires CD4 T cell-derived GM-CSF and activation of HIF-1α" @default.
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• W4200059543 doi "https://doi.org/10.1101/2021.12.16.473015" @default.
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