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

Abstract

Mice deficient for granulocyte-macrophage colony-stimulating factor (GM-CSF−/−) are highly susceptible to infection with Mycobacterium 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 intracellular M. tuberculosis growth. We have previously shown that GM-CSF produced by iNKT cells inhibits growth of M. 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 during M. tuberculosis infection. 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 of M. tuberculosis infection. However, GM-CSF is not required for T cell-mediated protection in settings where GM-CSF is produced by other cell types. Finally, using an in vitro macrophage infection model, we demonstrate that GM-CSF inhibition of M. tuberculosis growth 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 against M. tuberculosis.

Genetic Deficiency of Interferon‐γ Reveals Interferon‐γ–Independent Manifestations of Murine Hemophagocytic Lymphohistiocytosis

“…Given the differences between IFNγ‐sufficient and ‐deficient immunopathology, this model allowed the identification of some important IFNγ‐driven immunoregulatory networks. The elevated GM‐CSF was of particular interest to us given the extensive neutrophilia, the role of CD8+ T cells in driving disease, and the fact that GM‐CSF is made by CD8+ T cells . Indeed, we showed that IFNγ −/− Prf1 −/− mouse CD8+ T cells expressed elevated levels of GM‐CSF, and that exogenous administration of IFNγ regulated this production.…”

Myeloid‐derived suppressor cells: Roles in the tumor microenvironment and tumor radiotherapy

“…NK T cells (NKT cells) are a heterogeneous group of T cells that share properties of both T cells and NK cells. Upon stimulation, NKT cells can secrete plenty of IL‐4, IL‐13, IFN‐γ, GM‐CSF, and other cytokines and chemokines to display the antitumor and immune modulation activities . As reported, the secretion of TGF‐β by MDSCs inhibits the activation of NK cells by decreasing the expression of NKG2D .…”

Emerging role of γδ T cells in vaccine‐mediated protection from infectious diseases

“…These cells appear to be capable of directly killing extracellular Mtb via release of granulysin and intracellular Mtb via granulysin and perforin. 16 Clearly, the Vc9Vd2 T-cell subset is important in the human immune response to Mtb, but further work is required to evaluate the role of various cytokines in protection from disease at different timepoints during infection. 13 In the mouse model, although cd T cells seem to be less essential to immunity against Mtb, 14,15 GM-CSF production by cd T cells in the lungs seems to play a role in protection and an additive effect between GM-CSF and IFNc promoted macrophage control of intracellular bacterial replication.…”

“…13 In the mouse model, although cd T cells seem to be less essential to immunity against Mtb, 14,15 GM-CSF production by cd T cells in the lungs seems to play a role in protection and an additive effect between GM-CSF and IFNc promoted macrophage control of intracellular bacterial replication. 16 Clearly, the Vc9Vd2 T-cell subset is important in the human immune response to Mtb, but further work is required to evaluate the role of various cytokines in protection from disease at different timepoints during infection.…”