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Title: Low Levels of T Cell Exhaustion in Tuberculous Lung Granulomas

Abstract

The hallmarks of pulmonary Mycobacterium tuberculosis infection are lung granulomas. These organized structures are composed of host immune cells whose purpose is to contain or clear infection, creating a complex hub of immune and bacterial cell activity, as well as limiting pathology in the lungs. Yet, given cellular activity and the potential for frequent interactions between host immune cells and M. tuberculosis-infected cells, we observed a surprisingly low quantity of cytokine-producing T cells (<10% of granuloma T cells) in our recent study of M. tuberculosis infection within nonhuman primate (NHP) granulomas. Various mechanisms could limit T cell function, and one hypothesis is T cell exhaustion. T cell exhaustion is proposed to result from continual antigen stimulation, inducing them to enter a state characterized by low cytokine production, low proliferation, and expression of a series of inhibitory receptors, the most common being PD-1, LAG-3, and CTLA-4. In this work, we characterized the expression of inhibitory receptors on T cells and the functionality of these cells in tuberculosis (TB) lung granulomas. We then used these experimental data to calibrate and inform an agent-based computational model that captures environmental, cellular, and bacterial dynamics within granulomas in lungs during M. tuberculosis infection. Together, themore » results of the modeling and the experimental work suggest that T cell exhaustion alone is not responsible for the low quantity of M. tuberculosis-responsive T cells observed within TB granulomas and that the lack of exhaustion is likely an intrinsic property of granuloma structure.« less

Authors:
 [1];  [2];  [3];  [4];  [5];  [2]; ORCiD logo [1]
  1. Univ. of Pittsburgh, PA (United States), School of Medicine
  2. Univ. of Michigan, Ann Arbor, MI (United States). Dept. of Microbiology and Immunology
  3. Univ. of Pittsburgh, PA (United States). Dept. of Infectious Disease and Microbiology
  4. Univ. of Pittsburgh, PA (United States). Dept. of Lab. Animal Research
  5. Univ. of Pittsburgh, PA (United States). Dept. of Pediatrics
Publication Date:
Research Org.:
Lawrence Berkeley National Laboratory (LBNL), Berkeley, CA (United States). National Energy Research Scientific Computing Center (NERSC)
Sponsoring Org.:
USDOE Office of Science (SC)
OSTI Identifier:
1544219
Grant/Contract Number:  
AI123093; HL131072; HL110811; T32AI060525; MCB140228; AC02-05CH11231
Resource Type:
Accepted Manuscript
Journal Name:
Infection and Immunity
Additional Journal Information:
Journal Volume: 86; Journal Issue: 9; Journal ID: ISSN 0019-9567
Publisher:
American Society for Microbiology
Country of Publication:
United States
Language:
English
Subject:
60 APPLIED LIFE SCIENCES

Citation Formats

Wong, Eileen A., Joslyn, Louis, Grant, Nicole L., Klein, Edwin, Lin, Philana Ling, Kirschner, Denise E., and Flynn, JoAnne L. Low Levels of T Cell Exhaustion in Tuberculous Lung Granulomas. United States: N. p., 2018. Web. doi:10.1128/IAI.00426-18.
Wong, Eileen A., Joslyn, Louis, Grant, Nicole L., Klein, Edwin, Lin, Philana Ling, Kirschner, Denise E., & Flynn, JoAnne L. Low Levels of T Cell Exhaustion in Tuberculous Lung Granulomas. United States. doi:10.1128/IAI.00426-18.
Wong, Eileen A., Joslyn, Louis, Grant, Nicole L., Klein, Edwin, Lin, Philana Ling, Kirschner, Denise E., and Flynn, JoAnne L. Mon . "Low Levels of T Cell Exhaustion in Tuberculous Lung Granulomas". United States. doi:10.1128/IAI.00426-18. https://www.osti.gov/servlets/purl/1544219.
@article{osti_1544219,
title = {Low Levels of T Cell Exhaustion in Tuberculous Lung Granulomas},
author = {Wong, Eileen A. and Joslyn, Louis and Grant, Nicole L. and Klein, Edwin and Lin, Philana Ling and Kirschner, Denise E. and Flynn, JoAnne L.},
abstractNote = {The hallmarks of pulmonary Mycobacterium tuberculosis infection are lung granulomas. These organized structures are composed of host immune cells whose purpose is to contain or clear infection, creating a complex hub of immune and bacterial cell activity, as well as limiting pathology in the lungs. Yet, given cellular activity and the potential for frequent interactions between host immune cells and M. tuberculosis-infected cells, we observed a surprisingly low quantity of cytokine-producing T cells (<10% of granuloma T cells) in our recent study of M. tuberculosis infection within nonhuman primate (NHP) granulomas. Various mechanisms could limit T cell function, and one hypothesis is T cell exhaustion. T cell exhaustion is proposed to result from continual antigen stimulation, inducing them to enter a state characterized by low cytokine production, low proliferation, and expression of a series of inhibitory receptors, the most common being PD-1, LAG-3, and CTLA-4. In this work, we characterized the expression of inhibitory receptors on T cells and the functionality of these cells in tuberculosis (TB) lung granulomas. We then used these experimental data to calibrate and inform an agent-based computational model that captures environmental, cellular, and bacterial dynamics within granulomas in lungs during M. tuberculosis infection. Together, the results of the modeling and the experimental work suggest that T cell exhaustion alone is not responsible for the low quantity of M. tuberculosis-responsive T cells observed within TB granulomas and that the lack of exhaustion is likely an intrinsic property of granuloma structure.},
doi = {10.1128/IAI.00426-18},
journal = {Infection and Immunity},
number = 9,
volume = 86,
place = {United States},
year = {2018},
month = {6}
}

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