UMMS Affiliation

Department of Microbiology and Physiological Systems; UMass Metabolic Network

Publication Date

2017-10-24

Document Type

Article

Disciplines

Biochemistry | Cell Biology | Cellular and Molecular Physiology | Immunology and Infectious Disease | Microbiology | Molecular Biology

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 gammadelta 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 (PPARgamma). 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. tuberculosisIMPORTANCEMycobacterium tuberculosis is the bacterium that causes tuberculosis, the leading cause of death by any infection worldwide. T cells are critical components of the immune response to Mycobacterium tuberculosis While gamma interferon (IFN-gamma) is a key effector function of T cells during infection, a failed phase IIb clinical trial and other studies have revealed that IFN-gamma production alone is not sufficient to control M. tuberculosis In this study, we demonstrate that CD4(+), CD8(+), and nonconventional T cells produce GM-CSF during Mycobacterium tuberculosis infection 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 PPARgamma. The identification of GM-CSF production as a T cell effector function may inform future host-directed therapy or vaccine designs.

Keywords

GM-CSF, mycobacterium tuberculosis, T cells, cytokines, lung infection, macrophages

Rights and Permissions

Copyright © 2017 Rothchild et al. This is an open-access article distributed under the terms of the Creative Commons Attribution 4.0 International license.

DOI of Published Version

10.1128/mBio.01514-17

Source

MBio. 2017 Oct 24;8(5). pii: mBio.01514-17. doi: 10.1128/mBio.01514-17. Link to article on publisher's site

Journal/Book/Conference Title

mBio

Related Resources

Link to Article in PubMed

PubMed ID

29066547

Creative Commons License

Creative Commons Attribution 4.0 License
This work is licensed under a Creative Commons Attribution 4.0 License.

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