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Role of Granulocyte-Macrophage Colony-Stimulating Factor Production by T Cells during Mycobacterium tuberculosis Infection

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 peopl...

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Autores principales: Rothchild, Alissa C., Stowell, Britni, Goyal, Girija, Nunes-Alves, Cláudio, Yang, Qianting, Papavinasasundaram, Kadamba, Sassetti, Christopher M., Dranoff, Glenn, Chen, Xinchun, Lee, Jinhee, Behar, Samuel M.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: American Society for Microbiology 2017
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5654932/
https://www.ncbi.nlm.nih.gov/pubmed/29066547
http://dx.doi.org/10.1128/mBio.01514-17
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author Rothchild, Alissa C.
Stowell, Britni
Goyal, Girija
Nunes-Alves, Cláudio
Yang, Qianting
Papavinasasundaram, Kadamba
Sassetti, Christopher M.
Dranoff, Glenn
Chen, Xinchun
Lee, Jinhee
Behar, Samuel M.
author_facet Rothchild, Alissa C.
Stowell, Britni
Goyal, Girija
Nunes-Alves, Cláudio
Yang, Qianting
Papavinasasundaram, Kadamba
Sassetti, Christopher M.
Dranoff, Glenn
Chen, Xinchun
Lee, Jinhee
Behar, Samuel M.
author_sort Rothchild, Alissa C.
collection PubMed
description 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.
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spelling pubmed-56549322017-10-30 Role of Granulocyte-Macrophage Colony-Stimulating Factor Production by T Cells during Mycobacterium tuberculosis Infection Rothchild, Alissa C. Stowell, Britni Goyal, Girija Nunes-Alves, Cláudio Yang, Qianting Papavinasasundaram, Kadamba Sassetti, Christopher M. Dranoff, Glenn Chen, Xinchun Lee, Jinhee Behar, Samuel M. mBio Research Article 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. American Society for Microbiology 2017-10-24 /pmc/articles/PMC5654932/ /pubmed/29066547 http://dx.doi.org/10.1128/mBio.01514-17 Text en Copyright © 2017 Rothchild et al. https://creativecommons.org/licenses/by/4.0/ This is an open-access article distributed under the terms of the Creative Commons Attribution 4.0 International license (https://creativecommons.org/licenses/by/4.0/) .
spellingShingle Research Article
Rothchild, Alissa C.
Stowell, Britni
Goyal, Girija
Nunes-Alves, Cláudio
Yang, Qianting
Papavinasasundaram, Kadamba
Sassetti, Christopher M.
Dranoff, Glenn
Chen, Xinchun
Lee, Jinhee
Behar, Samuel M.
Role of Granulocyte-Macrophage Colony-Stimulating Factor Production by T Cells during Mycobacterium tuberculosis Infection
title Role of Granulocyte-Macrophage Colony-Stimulating Factor Production by T Cells during Mycobacterium tuberculosis Infection
title_full Role of Granulocyte-Macrophage Colony-Stimulating Factor Production by T Cells during Mycobacterium tuberculosis Infection
title_fullStr Role of Granulocyte-Macrophage Colony-Stimulating Factor Production by T Cells during Mycobacterium tuberculosis Infection
title_full_unstemmed Role of Granulocyte-Macrophage Colony-Stimulating Factor Production by T Cells during Mycobacterium tuberculosis Infection
title_short Role of Granulocyte-Macrophage Colony-Stimulating Factor Production by T Cells during Mycobacterium tuberculosis Infection
title_sort role of granulocyte-macrophage colony-stimulating factor production by t cells during mycobacterium tuberculosis infection
topic Research Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5654932/
https://www.ncbi.nlm.nih.gov/pubmed/29066547
http://dx.doi.org/10.1128/mBio.01514-17
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