Spatial Organization and Recruitment of Non-Specific T Cells May Limit T Cell-Macrophage Interactions Within Mycobacterium tuberculosis Granulomas
Tuberculosis (TB) is a worldwide health problem; successful interventions such as vaccines and treatment require a 2better understanding of the immune response to infection with Mycobacterium tuberculosis (Mtb). In many infectious diseases, pathogen-specific T cells that are recruited to infection s...
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Frontiers Media S.A.
2021
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oai:doaj.org-article:18bc1f958e4442d3b25681c8a9dfda802021-11-22T12:17:49ZSpatial Organization and Recruitment of Non-Specific T Cells May Limit T Cell-Macrophage Interactions Within Mycobacterium tuberculosis Granulomas1664-322410.3389/fimmu.2020.613638https://doaj.org/article/18bc1f958e4442d3b25681c8a9dfda802021-01-01T00:00:00Zhttps://www.frontiersin.org/articles/10.3389/fimmu.2020.613638/fullhttps://doaj.org/toc/1664-3224Tuberculosis (TB) is a worldwide health problem; successful interventions such as vaccines and treatment require a 2better understanding of the immune response to infection with Mycobacterium tuberculosis (Mtb). In many infectious diseases, pathogen-specific T cells that are recruited to infection sites are highly responsive and clear infection. Yet in the case of infection with Mtb, most individuals are unable to clear infection leading to either an asymptomatically controlled latent infection (the majority) or active disease (roughly 5%–10% of infections). The hallmark of Mtb infection is the recruitment of immune cells to lungs leading to development of multiple lung granulomas. Non-human primate models of TB indicate that on average <10% of T cells within granulomas are Mtb-responsive in terms of cytokine production. The reason for this reduced responsiveness is unknown and it may be at the core of why humans typically are unable to clear Mtb infection. There are a number of hypotheses as to why this reduced responsiveness may occur, including T cell exhaustion, direct downregulation of antigen presentation by Mtb within infected macrophages, the spatial organization of the granuloma itself, and/or recruitment of non-Mtb-specific T cells to lungs. We use a systems biology approach pairing data and modeling to dissect three of these hypotheses. We find that the structural organization of granulomas as well as recruitment of non-specific T cells likely contribute to reduced responsiveness.Jess A. MillarJess A. MillarJ. Russell ButlerStephanie EvansNicole L. GrantNicole L. GrantJoshua T. MattilaJennifer J. LindermanJoAnne L. FlynnDenise E. KirschnerFrontiers Media S.A.articleT cellmacrophageMycobacterium tuberculosislungcomputational modelgranulomaImmunologic diseases. AllergyRC581-607ENFrontiers in Immunology, Vol 11 (2021) |
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DOAJ |
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EN |
| topic |
T cell macrophage Mycobacterium tuberculosis lung computational model granuloma Immunologic diseases. Allergy RC581-607 |
| spellingShingle |
T cell macrophage Mycobacterium tuberculosis lung computational model granuloma Immunologic diseases. Allergy RC581-607 Jess A. Millar Jess A. Millar J. Russell Butler Stephanie Evans Nicole L. Grant Nicole L. Grant Joshua T. Mattila Jennifer J. Linderman JoAnne L. Flynn Denise E. Kirschner Spatial Organization and Recruitment of Non-Specific T Cells May Limit T Cell-Macrophage Interactions Within Mycobacterium tuberculosis Granulomas |
| description |
Tuberculosis (TB) is a worldwide health problem; successful interventions such as vaccines and treatment require a 2better understanding of the immune response to infection with Mycobacterium tuberculosis (Mtb). In many infectious diseases, pathogen-specific T cells that are recruited to infection sites are highly responsive and clear infection. Yet in the case of infection with Mtb, most individuals are unable to clear infection leading to either an asymptomatically controlled latent infection (the majority) or active disease (roughly 5%–10% of infections). The hallmark of Mtb infection is the recruitment of immune cells to lungs leading to development of multiple lung granulomas. Non-human primate models of TB indicate that on average <10% of T cells within granulomas are Mtb-responsive in terms of cytokine production. The reason for this reduced responsiveness is unknown and it may be at the core of why humans typically are unable to clear Mtb infection. There are a number of hypotheses as to why this reduced responsiveness may occur, including T cell exhaustion, direct downregulation of antigen presentation by Mtb within infected macrophages, the spatial organization of the granuloma itself, and/or recruitment of non-Mtb-specific T cells to lungs. We use a systems biology approach pairing data and modeling to dissect three of these hypotheses. We find that the structural organization of granulomas as well as recruitment of non-specific T cells likely contribute to reduced responsiveness. |
| format |
article |
| author |
Jess A. Millar Jess A. Millar J. Russell Butler Stephanie Evans Nicole L. Grant Nicole L. Grant Joshua T. Mattila Jennifer J. Linderman JoAnne L. Flynn Denise E. Kirschner |
| author_facet |
Jess A. Millar Jess A. Millar J. Russell Butler Stephanie Evans Nicole L. Grant Nicole L. Grant Joshua T. Mattila Jennifer J. Linderman JoAnne L. Flynn Denise E. Kirschner |
| author_sort |
Jess A. Millar |
| title |
Spatial Organization and Recruitment of Non-Specific T Cells May Limit T Cell-Macrophage Interactions Within Mycobacterium tuberculosis Granulomas |
| title_short |
Spatial Organization and Recruitment of Non-Specific T Cells May Limit T Cell-Macrophage Interactions Within Mycobacterium tuberculosis Granulomas |
| title_full |
Spatial Organization and Recruitment of Non-Specific T Cells May Limit T Cell-Macrophage Interactions Within Mycobacterium tuberculosis Granulomas |
| title_fullStr |
Spatial Organization and Recruitment of Non-Specific T Cells May Limit T Cell-Macrophage Interactions Within Mycobacterium tuberculosis Granulomas |
| title_full_unstemmed |
Spatial Organization and Recruitment of Non-Specific T Cells May Limit T Cell-Macrophage Interactions Within Mycobacterium tuberculosis Granulomas |
| title_sort |
spatial organization and recruitment of non-specific t cells may limit t cell-macrophage interactions within mycobacterium tuberculosis granulomas |
| publisher |
Frontiers Media S.A. |
| publishDate |
2021 |
| url |
https://doaj.org/article/18bc1f958e4442d3b25681c8a9dfda80 |
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