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Title: Deletion of TGF-β1 Increases Bacterial Clearance by Cytotoxic T Cells in a Tuberculosis Granuloma Model

Abstract

Mycobacterium tuberculosis is the pathogenic bacterium that causes tuberculosis (TB), one of the most lethal infectious diseases in the world. The only vaccine against TB is minimally protective, and multi-drug resistant TB necessitates new therapeutics to treat infection. Developing new therapies requires a better understanding of the complex host immune response to infection, including dissecting the processes leading to formation of granulomas, the dense cellular lesions associated with TB. In this work, we pair experimental and computational modeling studies to explore cytokine regulation in the context of TB. We use our next-generation hybrid multi-scale model of granuloma formation ( GranSim) to capture molecular, cellular, and tissue scale dynamics of granuloma formation. We identify TGF-β1 as a major inhibitor of cytotoxic T-cell effector function in granulomas. Deletion of TGF-β1 from the system results in improved bacterial clearance and lesion sterilization. We also identify a novel dichotomous regulation of cytotoxic T cells and macrophages by TGF-β1 and IL-10, respectively. These findings suggest that increasing cytotoxic T-cell effector functions may increase bacterial clearance in granulomas and highlight potential new therapeutic targets for treating TB.

Authors:
 [1];  [2];  [3];  [4];  [1]
  1. Univ. of Michigan Medical School, Ann Arbor, MI (United States). Dept. of Microbiology and Immunology
  2. Univ. of Michigan Medical School, Ann Arbor, MI (United States). Dept. of Microbiology and Immunology; Univ. of Michigan, Ann Arbor, MI (United States). Dept. of Chemical Engineering
  3. Univ. of Michigan, Ann Arbor, MI (United States). Dept. of Chemical Engineering
  4. Univ. of Pittsburgh Graduate School of Public Health, Pittsburg, PA (United States). Dept. of Infectious Diseases and Microbiology
Publication Date:
Research Org.:
Lawrence Berkeley National Lab. (LBNL), Berkeley, CA (United States). National Energy Research Scientific Computing Center
Sponsoring Org.:
USDOE Office of Science (SC)
OSTI Identifier:
1524079
Grant/Contract Number:  
AC02-05CH11231
Resource Type:
Accepted Manuscript
Journal Name:
Frontiers in Immunology
Additional Journal Information:
Journal Volume: 8; Journal ID: ISSN 1664-3224
Publisher:
Frontiers Research Foundation
Country of Publication:
United States
Language:
English
Subject:
cells-T cells; cytotoxic; infections-bacterial; transforming growth factor beta; tuberculosis; pulmonary; agent-based modeling

Citation Formats

Warsinske, Hayley C., Pienaar, Elsje, Linderman, Jennifer J., Mattila, Joshua T., and Kirschner, Denise E. Deletion of TGF-β1 Increases Bacterial Clearance by Cytotoxic T Cells in a Tuberculosis Granuloma Model. United States: N. p., 2017. Web. doi:10.3389/fimmu.2017.01843.
Warsinske, Hayley C., Pienaar, Elsje, Linderman, Jennifer J., Mattila, Joshua T., & Kirschner, Denise E. Deletion of TGF-β1 Increases Bacterial Clearance by Cytotoxic T Cells in a Tuberculosis Granuloma Model. United States. doi:10.3389/fimmu.2017.01843.
Warsinske, Hayley C., Pienaar, Elsje, Linderman, Jennifer J., Mattila, Joshua T., and Kirschner, Denise E. Wed . "Deletion of TGF-β1 Increases Bacterial Clearance by Cytotoxic T Cells in a Tuberculosis Granuloma Model". United States. doi:10.3389/fimmu.2017.01843. https://www.osti.gov/servlets/purl/1524079.
@article{osti_1524079,
title = {Deletion of TGF-β1 Increases Bacterial Clearance by Cytotoxic T Cells in a Tuberculosis Granuloma Model},
author = {Warsinske, Hayley C. and Pienaar, Elsje and Linderman, Jennifer J. and Mattila, Joshua T. and Kirschner, Denise E.},
abstractNote = {Mycobacterium tuberculosis is the pathogenic bacterium that causes tuberculosis (TB), one of the most lethal infectious diseases in the world. The only vaccine against TB is minimally protective, and multi-drug resistant TB necessitates new therapeutics to treat infection. Developing new therapies requires a better understanding of the complex host immune response to infection, including dissecting the processes leading to formation of granulomas, the dense cellular lesions associated with TB. In this work, we pair experimental and computational modeling studies to explore cytokine regulation in the context of TB. We use our next-generation hybrid multi-scale model of granuloma formation (GranSim) to capture molecular, cellular, and tissue scale dynamics of granuloma formation. We identify TGF-β1 as a major inhibitor of cytotoxic T-cell effector function in granulomas. Deletion of TGF-β1 from the system results in improved bacterial clearance and lesion sterilization. We also identify a novel dichotomous regulation of cytotoxic T cells and macrophages by TGF-β1 and IL-10, respectively. These findings suggest that increasing cytotoxic T-cell effector functions may increase bacterial clearance in granulomas and highlight potential new therapeutic targets for treating TB.},
doi = {10.3389/fimmu.2017.01843},
journal = {Frontiers in Immunology},
number = ,
volume = 8,
place = {United States},
year = {2017},
month = {12}
}

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