Role of Granulocyte-Macrophage Colony-Stimulating Factor Production by T Cells duringMycobacterium tuberculosisInfection

ABSTRACTMice deficient for granulocyte-macrophage colony-stimulating factor (GM-CSF−/−) are highly susceptible to infection withMycobacterium tuberculosis, and clinical data have shown that anti-GM-CSF neutralizing antibodies can lead to increased susceptibility to tuberculosis in otherwise healthy people. GM-CSF activates human and murine macrophages to inhibit intracellularM. tuberculosisgrowth. We have previously shown that GM-CSF produced by iNKT cells inhibits growth ofM. tuberculosis. However, the more general role of T cell-derived GM-CSF during infection has not been defined and how GM-CSF activates macrophages to inhibit bacterial growth is unknown. Here we demonstrate that, in addition to nonconventional T cells, conventional T cells also produce GM-CSF duringM. tuberculosisinfection. Early during infection, nonconventional iNKT cells and γδ T cells are the main source of GM-CSF, a role subsequently assumed by conventional CD4+T cells as the infection progresses.M. tuberculosis-specific T cells producing GM-CSF are also detected in the peripheral blood of infected people. Under conditions where nonhematopoietic production of GM-CSF is deficient, T cell production of GM-CSF is protective and required for control ofM. tuberculosisinfection. However, GM-CSF is not required for T cell-mediated protection in settings where GM-CSF is produced by other cell types. Finally, using anin vitromacrophage infection model, we demonstrate that GM-CSF inhibition ofM. tuberculosisgrowth requires the expression of peroxisome proliferator-activated receptor gamma (PPARγ). Thus, we identified GM-CSF production as a novel T cell effector function. These findings suggest that a strategy augmenting T cell production of GM-CSF could enhance host resistance againstM. tuberculosis.IMPORTANCEMycobacterium tuberculosisis the bacterium that causes tuberculosis, the leading cause of death by any infection worldwide. T cells are critical components of the immune response toMycobacterium tuberculosis. While gamma interferon (IFN-γ) is a key effector function of T cells during infection, a failed phase IIb clinical trial and other studies have revealed that IFN-γ production alone is not sufficient to controlM. tuberculosis. In this study, we demonstrate that CD4+, CD8+, and nonconventional T cells produce GM-CSF duringMycobacterium tuberculosisinfection in mice and in the peripheral blood of infected humans. Under conditions where other sources of GM-CSF are absent, T cell production of GM-CSF is protective and is required for control of infection. GM-CSF activation of macrophages to limit bacterial growth requires host expression of the transcription factor PPARγ. The identification of GM-CSF production as a T cell effector function may inform future host-directed therapy or vaccine designs.