Role of Granulocyte-Macrophage Colony-Stimulating Factor Production by T Cells during <italic toggle="yes">Mycobacterium tuberculosis</italic> Infection
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 health...
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American Society for Microbiology
2017
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oai:doaj.org-article:84fda4d38ff444bc83d207a27981150e2021-11-15T15:51:51ZRole of Granulocyte-Macrophage Colony-Stimulating Factor Production by T Cells during <italic toggle="yes">Mycobacterium tuberculosis</italic> Infection10.1128/mBio.01514-172150-7511https://doaj.org/article/84fda4d38ff444bc83d207a27981150e2017-11-01T00:00:00Zhttps://journals.asm.org/doi/10.1128/mBio.01514-17https://doaj.org/toc/2150-7511ABSTRACT 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. IMPORTANCE Mycobacterium 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-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 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 PPARγ. The identification of GM-CSF production as a T cell effector function may inform future host-directed therapy or vaccine designs.Alissa C. RothchildBritni StowellGirija GoyalCláudio Nunes-AlvesQianting YangKadamba PapavinasasundaramChristopher M. SassettiGlenn DranoffXinchun ChenJinhee LeeSamuel M. BeharAmerican Society for MicrobiologyarticleGM-CSFMycobacterium tuberculosisT cellscytokineslung infectionmacrophagesMicrobiologyQR1-502ENmBio, Vol 8, Iss 5 (2017) |
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DOAJ |
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EN |
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GM-CSF Mycobacterium tuberculosis T cells cytokines lung infection macrophages Microbiology QR1-502 |
| spellingShingle |
GM-CSF Mycobacterium tuberculosis T cells cytokines lung infection macrophages Microbiology QR1-502 Alissa C. Rothchild Britni Stowell Girija Goyal Cláudio Nunes-Alves Qianting Yang Kadamba Papavinasasundaram Christopher M. Sassetti Glenn Dranoff Xinchun Chen Jinhee Lee Samuel M. Behar Role of Granulocyte-Macrophage Colony-Stimulating Factor Production by T Cells during <italic toggle="yes">Mycobacterium tuberculosis</italic> Infection |
| description |
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. IMPORTANCE Mycobacterium 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-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 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 PPARγ. The identification of GM-CSF production as a T cell effector function may inform future host-directed therapy or vaccine designs. |
| format |
article |
| author |
Alissa C. Rothchild Britni Stowell Girija Goyal Cláudio Nunes-Alves Qianting Yang Kadamba Papavinasasundaram Christopher M. Sassetti Glenn Dranoff Xinchun Chen Jinhee Lee Samuel M. Behar |
| author_facet |
Alissa C. Rothchild Britni Stowell Girija Goyal Cláudio Nunes-Alves Qianting Yang Kadamba Papavinasasundaram Christopher M. Sassetti Glenn Dranoff Xinchun Chen Jinhee Lee Samuel M. Behar |
| author_sort |
Alissa C. Rothchild |
| title |
Role of Granulocyte-Macrophage Colony-Stimulating Factor Production by T Cells during <italic toggle="yes">Mycobacterium tuberculosis</italic> Infection |
| title_short |
Role of Granulocyte-Macrophage Colony-Stimulating Factor Production by T Cells during <italic toggle="yes">Mycobacterium tuberculosis</italic> Infection |
| title_full |
Role of Granulocyte-Macrophage Colony-Stimulating Factor Production by T Cells during <italic toggle="yes">Mycobacterium tuberculosis</italic> Infection |
| title_fullStr |
Role of Granulocyte-Macrophage Colony-Stimulating Factor Production by T Cells during <italic toggle="yes">Mycobacterium tuberculosis</italic> Infection |
| title_full_unstemmed |
Role of Granulocyte-Macrophage Colony-Stimulating Factor Production by T Cells during <italic toggle="yes">Mycobacterium tuberculosis</italic> Infection |
| title_sort |
role of granulocyte-macrophage colony-stimulating factor production by t cells during <italic toggle="yes">mycobacterium tuberculosis</italic> infection |
| publisher |
American Society for Microbiology |
| publishDate |
2017 |
| url |
https://doaj.org/article/84fda4d38ff444bc83d207a27981150e |
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