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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 Lab. (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}
}

Journal Article:
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Cited by: 6 works
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Figures / Tables:

FIG 1 FIG 1: Few T cells in granulomas of M. tuberculosis-infected macaques coexpress inhibitory receptors. (A) Frequency of CD3+ cells expressing inhibitory receptors PD-1, CTLA-4, or LAG-3 in individual granulomas from M. tuberculosis-infected cynomolgus or rhesus macaques. (B) CD4 T cells express inhibitory receptors more frequently than CD8 T cells. Pmore » values indicated on the figure were determined by a Wilcoxon matched-pairs signed-rank test. (C) Frequency of coexpression of inhibitory receptors in granulomas. Each point indicates a granuloma, each color corresponds to an NHP (12 NHPs), circles indicate cynomolgus macaques, and squares indicate rhesus macaques. (D) Clusters of granulomas and TB pneumonia samples have similarly low frequencies of CTLA-4 and LAG3 and similarly high frequencies of PD-1 alone. There is low coexpression of inhibitory receptors in clusters of granulomas. Each point indicates a cluster, consolidation, or pneumonia lung sample, each color corresponds to an NHP (6 NHPs), circles indicate cynomolgus macaques, squares indicate rhesus macaques, and the diamond indicates a TB pneumonia sample. Horizontal lines indicate medians.« less

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Works referenced in this record:

A methodology for performing global uncertainty and sensitivity analysis in systems biology
journal, September 2008

  • Marino, Simeone; Hogue, Ian B.; Ray, Christian J.
  • Journal of Theoretical Biology, Vol. 254, Issue 1
  • DOI: 10.1016/j.jtbi.2008.04.011

Upregulation of PD-1 expression on HIV-specific CD8+ T cells leads to reversible immune dysfunction
journal, August 2006

  • Trautmann, Lydie; Janbazian, Loury; Chomont, Nicolas
  • Nature Medicine, Vol. 12, Issue 10
  • DOI: 10.1038/nm1482

Programmed death-1 (PD-1)-deficient mice are extraordinarily sensitive to tuberculosis
journal, July 2010

  • Lazar-Molnar, E.; Chen, B.; Sweeney, K. A.
  • Proceedings of the National Academy of Sciences, Vol. 107, Issue 30
  • DOI: 10.1073/pnas.1007394107

Differences in Reactivation of Tuberculosis Induced from Anti-TNF Treatments Are Based on Bioavailability in Granulomatous Tissue
journal, January 2007


CD4+ T cells with an activated and exhausted phenotype distinguish immunodeficiency during aviremic HIV-2 infection
journal, January 2016


Activation drives PD-1 expression during vaccine-specific proliferation and following lentiviral infection in macaques
journal, May 2008

  • Hokey, David A.; Johnson, F. Brad; Smith, Jasmine
  • European Journal of Immunology, Vol. 38, Issue 5
  • DOI: 10.1002/eji.200737857

Viral Persistence Alters CD8 T-Cell Immunodominance and Tissue Distribution and Results in Distinct Stages of Functional Impairment
journal, April 2003


Systems biology approaches for understanding cellular mechanisms of immunity in lymph nodes during infection
journal, October 2011

  • Mirsky, Henry P.; Miller, Mark J.; Linderman, Jennifer J.
  • Journal of Theoretical Biology, Vol. 287
  • DOI: 10.1016/j.jtbi.2011.06.037

Multiscale Computational Modeling Reveals a Critical Role for TNF-α Receptor 1 Dynamics in Tuberculosis Granuloma Formation
journal, February 2011

  • Fallahi-Sichani, Mohammad; El-Kebir, Mohammed; Marino, Simeone
  • The Journal of Immunology, Vol. 186, Issue 6
  • DOI: 10.4049/jimmunol.1003299

High antigen levels induce an exhausted phenotype in a chronic infection without impairing T cell expansion and survival
journal, July 2016

  • Utzschneider, Daniel T.; Alfei, Francesca; Roelli, Patrick
  • The Journal of Experimental Medicine, Vol. 213, Issue 9
  • DOI: 10.1084/jem.20150598

A computational tool integrating host immunity with antibiotic dynamics to study tuberculosis treatment
journal, February 2015

  • Pienaar, Elsje; Cilfone, Nicholas A.; Lin, Philana Ling
  • Journal of Theoretical Biology, Vol. 367
  • DOI: 10.1016/j.jtbi.2014.11.021

TIM3 Mediates T Cell Exhaustion during Mycobacterium tuberculosis Infection
journal, March 2016


T-cell exhaustion due to persistent antigen: Quantity not quality?: HIGHLIGHTS
journal, September 2012

  • Zuniga, Elina I.; Harker, James A.
  • European Journal of Immunology, Vol. 42, Issue 9
  • DOI: 10.1002/eji.201242852

Synergy between Individual TNF-Dependent Functions Determines Granuloma Performance for Controlling Mycobacterium tuberculosis Infection
journal, March 2009

  • Ray, J. Christian J.; Flynn, JoAnne L.; Kirschner, Denise E.
  • The Journal of Immunology, Vol. 182, Issue 6
  • DOI: 10.4049/jimmunol.0802297

Coregulation of CD8+ T cell exhaustion by multiple inhibitory receptors during chronic viral infection
journal, November 2008

  • Blackburn, Shawn D.; Shin, Haina; Haining, W. Nicholas
  • Nature Immunology, Vol. 10, Issue 1
  • DOI: 10.1038/ni.1679

Understanding Latent Tuberculosis: A Moving Target
journal, June 2010


Who puts the tubercle in tuberculosis?
journal, December 2006


Differential Risk of Tuberculosis Reactivation among Anti-TNF Therapies Is Due to Drug Binding Kinetics and Permeability
journal, February 2012

  • Fallahi-Sichani, Mohammad; Flynn, JoAnne L.; Linderman, Jennifer J.
  • The Journal of Immunology, Vol. 188, Issue 7
  • DOI: 10.4049/jimmunol.1103298

Early Events in Mycobacterium tuberculosis Infection in Cynomolgus Macaques
journal, June 2006

  • Lin, P. L.; Pawar, S.; Myers, A.
  • Infection and Immunity, Vol. 74, Issue 7
  • DOI: 10.1128/IAI.00064-06

PD-1 expression on HIV-specific T cells is associated with T-cell exhaustion and disease progression
journal, August 2006

  • Day, Cheryl L.; Kaufmann, Daniel E.; Kiepiela, Photini
  • Nature, Vol. 443, Issue 7109
  • DOI: 10.1038/nature05115

LAG-3, a novel lymphocyte activation gene closely related to CD4
journal, May 1990


Rhesus Macaques Are More Susceptible to Progressive Tuberculosis than Cynomolgus Macaques: a Quantitative Comparison
journal, September 2017

  • Maiello, Pauline; DiFazio, Robert M.; Cadena, Anthony M.
  • Infection and Immunity, Vol. 86, Issue 2
  • DOI: 10.1128/IAI.00505-17

Characterization of Hepatitis B Virus (HBV)-Specific T-Cell Dysfunction in Chronic HBV Infection
journal, February 2007

  • Boni, C.; Fisicaro, P.; Valdatta, C.
  • Journal of Virology, Vol. 81, Issue 8
  • DOI: 10.1128/JVI.02844-06

PD-1 Expression in Acute Hepatitis C Virus (HCV) Infection Is Associated with HCV-Specific CD8 Exhaustion
journal, September 2006


Functional Capacity of Mycobacterium tuberculosis -Specific T Cell Responses in Humans Is Associated with Mycobacterial Load
journal, July 2011

  • Day, Cheryl L.; Abrahams, Deborah A.; Lerumo, Lesedi
  • The Journal of Immunology, Vol. 187, Issue 5
  • DOI: 10.4049/jimmunol.1101122

LAG3 Expression in Active Mycobacterium tuberculosis Infections
journal, March 2015

  • Phillips, Bonnie L.; Mehra, Smriti; Ahsan, Muhammad H.
  • The American Journal of Pathology, Vol. 185, Issue 3
  • DOI: 10.1016/j.ajpath.2014.11.003

Enhancing SIV-specific immunity in vivo by PD-1 blockade
journal, December 2008

  • Velu, Vijayakumar; Titanji, Kehmia; Zhu, Baogong
  • Nature, Vol. 458, Issue 7235
  • DOI: 10.1038/nature07662

LAG-3 Regulates Plasmacytoid Dendritic Cell Homeostasis
journal, February 2009

  • Workman, Creg J.; Wang, Yao; El Kasmi, Karim C.
  • The Journal of Immunology, Vol. 182, Issue 4
  • DOI: 10.4049/jimmunol.0800185

Deletion of TGF-β1 Increases Bacterial Clearance by Cytotoxic T Cells in a Tuberculosis Granuloma Model
journal, December 2017

  • Warsinske, Hayley C.; Pienaar, Elsje; Linderman, Jennifer J.
  • Frontiers in Immunology, Vol. 8
  • DOI: 10.3389/fimmu.2017.01843

NF-κB Signaling Dynamics Play a Key Role in Infection Control in Tuberculosis
journal, January 2012

  • Fallahi-Sichani, Mohammad; Kirschner, Denise E.; Linderman, Jennifer J.
  • Frontiers in Physiology, Vol. 3
  • DOI: 10.3389/fphys.2012.00170

Viral Immune Evasion Due to Persistence of Activated T Cells Without Effector Function
journal, December 1998

  • Zajac, Allan J.; Blattman, Joseph N.; Murali-Krishna, Kaja
  • The Journal of Experimental Medicine, Vol. 188, Issue 12
  • DOI: 10.1084/jem.188.12.2205

In Vivo Blockade of the Programmed Cell Death-1 Pathway Using Soluble Recombinant PD-1-Fc Enhances CD4 + and CD8 + T Cell Responses but Has Limited Clinical Benefit
journal, November 2013

  • Amancha, Praveen K.; Hong, Jung Joo; Rogers, Kenneth
  • The Journal of Immunology, Vol. 191, Issue 12
  • DOI: 10.4049/jimmunol.1302044

CD8 + T Cell Exhaustion, Suppressed Gamma Interferon Production, and Delayed Memory Response Induced by Chronic Brucella melitensis Infection
journal, September 2015

  • Durward-Diioia, Marina; Harms, Jerome; Khan, Mike
  • Infection and Immunity, Vol. 83, Issue 12
  • DOI: 10.1128/IAI.01184-15

The Granuloma in Tuberculosis: Dynamics of a Host–Pathogen Collusion
journal, January 2013


Macrophages and control of granulomatous inflammation in tuberculosis
journal, March 2011

  • Flynn, J. L.; Chan, J.; Lin, P. L.
  • Mucosal Immunology, Vol. 4, Issue 3
  • DOI: 10.1038/mi.2011.14

Programmed Death 1 Expression on HIV-Specific CD4 + T Cells Is Driven by Viral Replication and Associated with T Cell Dysfunction
journal, July 2007

  • D’Souza, Michelle; Fontenot, Andrew P.; Mack, Doug G.
  • The Journal of Immunology, Vol. 179, Issue 3
  • DOI: 10.4049/jimmunol.179.3.1979

T Cells from Programmed Death-1 Deficient Mice Respond Poorly to Mycobacterium tuberculosis Infection
journal, May 2011


The blockade of immune checkpoints in cancer immunotherapy
journal, March 2012

  • Pardoll, Drew M.
  • Nature Reviews Cancer, Vol. 12, Issue 4
  • DOI: 10.1038/nrc3239

Programmed Death (PD)-1:PD-Ligand 1/PD-Ligand 2 Pathway Inhibits T Cell Effector Functions during Human Tuberculosis
journal, June 2008

  • Jurado, Javier O.; Alvarez, Ivana B.; Pasquinelli, Virginia
  • The Journal of Immunology, Vol. 181, Issue 1
  • DOI: 10.4049/jimmunol.181.1.116

T-cell exhaustion: characteristics, causes and conversion: T-cell exhaustion
journal, February 2010


Integrated Transcriptomics Establish Macrophage Polarization Signatures and have Potential Applications for Clinical Health and Disease
journal, August 2015

  • Becker, Matheus; De Bastiani, Marco A.; Parisi, Mariana M.
  • Scientific Reports, Vol. 5, Issue 1
  • DOI: 10.1038/srep13351

Identifying control mechanisms of granuloma formation during M. tuberculosis infection using an agent-based model
journal, December 2004

  • Segovia-Juarez, Jose L.; Ganguli, Suman; Kirschner, Denise
  • Journal of Theoretical Biology, Vol. 231, Issue 3
  • DOI: 10.1016/j.jtbi.2004.06.031

The timing of TNF and IFN-γ signaling affects macrophage activation strategies during Mycobacterium tuberculosis infection
journal, May 2008


A comparison of random vs. chemotaxis-driven contacts of T cells with dendritic cells during repertoire scanning
journal, February 2008

  • Riggs, Thomas; Walts, Adrienne; Perry, Nicolas
  • Journal of Theoretical Biology, Vol. 250, Issue 4
  • DOI: 10.1016/j.jtbi.2007.10.015

Identification of Key Processes that Control Tumor Necrosis Factor Availability in a Tuberculosis Granuloma
journal, May 2010

  • Fallahi-Sichani, Mohammad; Schaller, Matthew A.; Kirschner, Denise E.
  • PLoS Computational Biology, Vol. 6, Issue 5
  • DOI: 10.1371/journal.pcbi.1000778

T cell exhaustion
journal, May 2011


Restoring function in exhausted CD8 T cells during chronic viral infection
journal, December 2005

  • Barber, Daniel L.; Wherry, E. John; Masopust, David
  • Nature, Vol. 439, Issue 7077
  • DOI: 10.1038/nature04444

Anti-TIM3 Antibody Promotes T Cell IFN- -Mediated Antitumor Immunity and Suppresses Established Tumors
journal, March 2011


PD-1/PD-L pathway inhibits M.tb-specific CD4+ T-cell functions and phagocytosis of macrophages in active tuberculosis
journal, December 2016

  • Shen, Lei; Gao, Yan; Liu, Yuanyuan
  • Scientific Reports, Vol. 6, Issue 1
  • DOI: 10.1038/srep38362

Re-Evaluation of PD-1 Expression by T Cells as a Marker for Immune Exhaustion during SIV Infection
journal, March 2013


Variability in Tuberculosis Granuloma T Cell Responses Exists, but a Balance of Pro- and Anti-inflammatory Cytokines Is Associated with Sterilization
journal, January 2015


Microenvironments in Tuberculous Granulomas Are Delineated by Distinct Populations of Macrophage Subsets and Expression of Nitric Oxide Synthase and Arginase Isoforms
journal, June 2013

  • Mattila, Joshua T.; Ojo, Olabisi O.; Kepka-Lenhart, Diane
  • The Journal of Immunology, Vol. 191, Issue 2
  • DOI: 10.4049/jimmunol.1300113

Molecular and Transcriptional Basis of CD4+ T Cell Dysfunction during Chronic Infection
journal, February 2014


CD4 T Cells Promote Rather than Control Tuberculosis in the Absence of PD-1–Mediated Inhibition
journal, December 2010

  • Barber, Daniel L.; Mayer-Barber, Katrin D.; Feng, Carl G.
  • The Journal of Immunology, Vol. 186, Issue 3
  • DOI: 10.4049/jimmunol.1003304

Chronic Antigen Stimulation Alone Is Sufficient to Drive CD8 + T Cell Exhaustion
journal, May 2009

  • Bucks, Christine M.; Norton, Jillian A.; Boesteanu, Alina C.
  • The Journal of Immunology, Vol. 182, Issue 11
  • DOI: 10.4049/jimmunol.0800997

Quantitative Comparison of Active and Latent Tuberculosis in the Cynomolgus Macaque Model
journal, July 2009

  • Lin, P. L.; Rodgers, M.; Smith, L.
  • Infection and Immunity, Vol. 77, Issue 10
  • DOI: 10.1128/IAI.00592-09

Expression of lymphocyte activation gene 3 (LAG-3) on B cells is induced by T cells
journal, July 2005

  • Kisielow, Malgorzata; Kisielow, Jan; Capoferri-Sollami, Giuseppina
  • European Journal of Immunology, Vol. 35, Issue 7
  • DOI: 10.1002/eji.200526090

Distinct functions of antigen-specific CD4 T cells during murine Mycobacterium tuberculosis infection
journal, October 2010

  • Reiley, W. W.; Shafiani, S.; Wittmer, S. T.
  • Proceedings of the National Academy of Sciences, Vol. 107, Issue 45
  • DOI: 10.1073/pnas.1006298107

T-cell exhaustion in the tumor microenvironment
journal, June 2015


Chemokines enhance immunity by guiding naive CD8+ T cells to sites of CD4+ T cell–dendritic cell interaction
journal, April 2006

  • Castellino, Flora; Huang, Alex Y.; Altan-Bonnet, Grégoire
  • Nature, Vol. 440, Issue 7086
  • DOI: 10.1038/nature04651

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    Agent‐based models of inflammation in translational systems biology: A decade later
    journal, June 2019

    • Vodovotz, Yoram; An, Gary
    • Wiley Interdisciplinary Reviews: Systems Biology and Medicine, Vol. 11, Issue 6
    • DOI: 10.1002/wsbm.1460

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