skip to main content
DOE PAGES title logo U.S. Department of Energy
Office of Scientific and Technical Information

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:
59 BASIC BIOLOGICAL SCIENCES; 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}
}

Journal Article:
Free Publicly Available Full Text
Publisher's Version of Record

Citation Metrics:
Cited by: 11 works
Citation information provided by
Web of Science

Figures / Tables:

Table 1 Table 1: Categories of simulated granulomas by bacterial status.

Save / Share:

Works referenced in this record:

An essential role for interferon gamma in resistance to Mycobacterium tuberculosis infection
journal, December 1993


Chemokine stimulation of monocyte matrix metalloproteinase-9 requires endogenous TNF-α
journal, February 2002


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

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


A hybrid multi-compartment model of granuloma formation and T cell priming in Tuberculosis
journal, July 2011

  • Marino, Simeone; El-Kebir, Mohammed; Kirschner, Denise
  • Journal of Theoretical Biology, Vol. 280, Issue 1
  • DOI: 10.1016/j.jtbi.2011.03.022

Fibrosis in connective tissue disease: the role of the myofibroblast and fibroblast-epithelial cell interactions
journal, January 2007

  • Krieg, Thomas; Abraham, David; Lafyatis, Robert
  • Arthritis Research & Therapy, Vol. 9, Issue Suppl 2
  • DOI: 10.1186/ar2188

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

Lack of IL-10 alters inflammatory and immune responses during pulmonary Mycobacterium tuberculosis infection
journal, March 2009

  • Higgins, David M.; Sanchez-Campillo, Joaquin; Rosas-Taraco, Adrian G.
  • Tuberculosis, Vol. 89, Issue 2
  • DOI: 10.1016/j.tube.2009.01.001

Increased inflammatory cytokines and new collagen formation in cutaneous tuberculosis and sarcoidosis.
journal, December 1996


Understanding the Immune Response in Tuberculosis Using Different Mathematical Models and Biological Scales
journal, January 2005

  • Gammack, David; Ganguli, Suman; Marino, Simeone
  • Multiscale Modeling & Simulation, Vol. 3, Issue 2
  • DOI: 10.1137/040603127

Radiologic Responses in Cynomolgus Macaques for Assessing Tuberculosis Chemotherapy Regimens
journal, June 2013

  • Lin, Philana Ling; Coleman, Teresa; Carney, Jonathan P. J.
  • Antimicrobial Agents and Chemotherapy, Vol. 57, Issue 9
  • DOI: 10.1128/AAC.00277-13

In silico evaluation and exploration of antibiotic tuberculosis treatment regimens
journal, November 2015

  • Pienaar, Elsje; Dartois, Véronique; Linderman, Jennifer J.
  • BMC Systems Biology, Vol. 9, Issue 1
  • DOI: 10.1186/s12918-015-0221-8

Tumor Necrosis Factor Blockers Influence Macrophage Responses to Mycobacterium tuberculosis
journal, December 2008

  • Harris, James; Hope, Jayne. C.; Keane, Joseph
  • The Journal of Infectious Diseases, Vol. 198, Issue 12
  • DOI: 10.1086/593174

I MMUNOLOGY OF T UBERCULOSIS
journal, April 2001


TGF-β type II receptor–deficient thymocytes develop normally but demonstrate increased CD8+ proliferation in vivo
journal, December 2005


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

Transforming growth factor β1 regulation of macrophage activation depends on the triggering stimulus
journal, November 1993

  • Corradin, Sally Betz; Buchmuller-Rouiller, Yolande; Smith, Josiane
  • Journal of Leukocyte Biology, Vol. 54, Issue 5
  • DOI: 10.1002/jlb.54.5.423

TGF-β stimulation in human and murine cells reveals commonly affected biological processes and pathways at transcription level
journal, January 2014

  • Abnaof, Khalid; Mallela, Nikhil; Walenda, Gudrun
  • BMC Systems Biology, Vol. 8, Issue 1
  • DOI: 10.1186/1752-0509-8-55

Cross-modulation by transforming growth factor beta in human tuberculosis: suppression of antigen-driven blastogenesis and interferon gamma production.
journal, April 1996

  • Hirsch, C. S.; Hussain, R.; Toossi, Z.
  • Proceedings of the National Academy of Sciences, Vol. 93, Issue 8
  • DOI: 10.1073/pnas.93.8.3193

Mycobacterium tuberculosis : success through dormancy
journal, May 2012


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

The Immune Response in Tuberculosis
journal, March 2013


Identifying Mechanisms of Homeostatic Signaling in Fibroblast Differentiation
journal, August 2015

  • Warsinske, Hayley C.; Ashley, Shanna L.; Linderman, Jennifer J.
  • Bulletin of Mathematical Biology, Vol. 77, Issue 8
  • DOI: 10.1007/s11538-015-0096-2

Enhancement Of Intracellular Growth Of Mycobacterium Tuberculosis In Human Monocytes by Transforming Growth Factor- l
journal, November 1994


Selective inhibition of growth-related gene expression in murine keratinocytes by transforming growth factor beta.
journal, August 1988

  • Coffey, R. J.; Bascom, C. C.; Sipes, N. J.
  • Molecular and Cellular Biology, Vol. 8, Issue 8
  • DOI: 10.1128/MCB.8.8.3088

Enhanced protection to Mycobacterium tuberculosis infection in IL-10-deficient mice is accompanied by early and enhanced Th1 responses in the lung
journal, June 2010

  • Redford, Paul S.; Boonstra, Andre; Read, Simon
  • European Journal of Immunology, Vol. 40, Issue 8
  • DOI: 10.1002/eji.201040433

Tuberculosis: Latency and Reactivation
journal, July 2001


Tuneable resolution as a systems biology approach for multi-scale, multi-compartment computational models: Tuneable resolution as a systems biology approach
journal, July 2014

  • Kirschner, Denise E.; Hunt, C. Anthony; Marino, Simeone
  • Wiley Interdisciplinary Reviews: Systems Biology and Medicine, Vol. 6, Issue 4
  • DOI: 10.1002/wsbm.1270

Tumor necrosis factor-α is required in the protective immune response against mycobacterium tuberculosis in mice
journal, June 1995


TNF neutralization results in disseminated disease during acute and latent M. tuberculosis infection with normal granuloma structure
journal, January 2010

  • Lin, Philana Ling; Myers, Amy; Smith, Le'Kneitah
  • Arthritis & Rheumatism
  • DOI: 10.1002/art.27271

TGF-β directly targets cytotoxic T cell functions during tumor evasion of immune surveillance
journal, November 2005


The Role of TGFβ in the Pathogenesis of Human Tuberculosis
journal, May 1998

  • Toossi, Zahra; Ellner, Jerrold J.
  • Clinical Immunology and Immunopathology, Vol. 87, Issue 2
  • DOI: 10.1006/clin.1998.4528

Transforming growth factor-β controls T helper type 1 cell development through regulation of natural killer cell interferon-γ
journal, April 2005

  • Laouar, Yasmina; Sutterwala, Fayyaz S.; Gorelik, Leonid
  • Nature Immunology, Vol. 6, Issue 6
  • DOI: 10.1038/ni1197

Immunoregulation of dendritic cells by IL-10 is mediated through suppression of the PI3K/Akt pathway and of IκB kinase activity
journal, August 2004


TGF-β is responsible for NK cell immaturity during ontogeny and increased susceptibility to infection during mouse infancy
journal, August 2012

  • Marcoe, Jeffrey P.; Lim, James R.; Schaubert, Keri L.
  • Nature Immunology, Vol. 13, Issue 9
  • DOI: 10.1038/ni.2388

Inflammatory signaling in human tuberculosis granulomas is spatially organized
journal, April 2016

  • Marakalala, Mohlopheni J.; Raju, Ravikiran M.; Sharma, Kirti
  • Nature Medicine, Vol. 22, Issue 5
  • DOI: 10.1038/nm.4073

Multiscale Model of Mycobacterium tuberculosis Infection Maps Metabolite and Gene Perturbations to Granuloma Sterilization Predictions
journal, March 2016

  • Pienaar, Elsje; Matern, William M.; Linderman, Jennifer J.
  • Infection and Immunity, Vol. 84, Issue 5
  • DOI: 10.1128/IAI.01438-15

Lessons from experimental Mycobacterium tuberculosis infections
journal, April 2006


Regulatory T cells suppress tumor-specific CD8 T cell cytotoxicity through TGF-  signals in vivo
journal, December 2004

  • Chen, M. -L.; Pittet, M. J.; Gorelik, L.
  • Proceedings of the National Academy of Sciences, Vol. 102, Issue 2
  • DOI: 10.1073/pnas.0408197102

The human immune response to Mycobacterium tuberculosis in lung and lymph node
journal, April 2004


Exploring the full spectrum of macrophage activation
journal, December 2008

  • Mosser, David M.; Edwards, Justin P.
  • Nature Reviews Immunology, Vol. 8, Issue 12
  • DOI: 10.1038/nri2448

The transforming growth factor-β superfamily of receptors
journal, February 2004


Interleukin 10(IL-10) inhibits cytokine synthesis by human monocytes: an autoregulatory role of IL-10 produced by monocytes
journal, November 1991


Exposure to pro-inflammatory cytokines upregulates MMP-9 synthesis by mesenchymal stem cells-derived osteoprogenitors
journal, February 2008

  • Ben David, D.; Reznick, A. Z.; Srouji, S.
  • Histochemistry and Cell Biology, Vol. 129, Issue 5
  • DOI: 10.1007/s00418-008-0391-1

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

The Hypervirulent Mycobacterium tuberculosis Strain HN878 Induces a Potent TH1 Response followed by Rapid Down-Regulation
journal, June 2007

  • Ordway, Diane; Henao-Tamayo, Marcela; Harton, Marisa
  • The Journal of Immunology, Vol. 179, Issue 1
  • DOI: 10.4049/jimmunol.179.1.522

TNF and IL-10 are major factors in modulation of the phagocytic cell environment in lung and lymph node in tuberculosis: A next-generation two-compartmental model
journal, August 2010


Transforming growth factor-beta suppresses interferon-gamma-induced toxoplasmastatic activity in murine macrophages by inhibition of tumour necrosis factor-alpha production
journal, April 2001


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

A deletion defining a common Asian lineage of Mycobacterium tuberculosis associates with immune subversion
journal, October 2006

  • Newton, S. M.; Smith, R. J.; Wilkinson, K. A.
  • Proceedings of the National Academy of Sciences, Vol. 103, Issue 42
  • DOI: 10.1073/pnas.0604283103

Regulation and Functions of the IL-10 Family of Cytokines in Inflammation and Disease
journal, April 2011


The role of IL-10 in immune regulation during M. tuberculosis infection
journal, March 2011

  • Redford, P. S.; Murray, P. J.; O'Garra, A.
  • Mucosal Immunology, Vol. 4, Issue 3
  • DOI: 10.1038/mi.2011.7

The association between sterilizing activity and drug distribution into tuberculosis lesions
journal, September 2015

  • Prideaux, Brendan; Via, Laura E.; Zimmerman, Matthew D.
  • Nature Medicine, Vol. 21, Issue 10
  • DOI: 10.1038/nm.3937

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

Immunology studies in non-human primate models of tuberculosis
journal, February 2015

  • Flynn, JoAnne L.; Gideon, Hannah P.; Mattila, Joshua T.
  • Immunological Reviews, Vol. 264, Issue 1
  • DOI: 10.1111/imr.12258

TNF Influences Chemokine Expression of Macrophages In Vitro and That of CD11b + Cells In Vivo during Mycobacterium tuberculosis Infection
journal, May 2004


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


Sterilization of granulomas is common in active and latent tuberculosis despite within-host variability in bacterial killing
journal, December 2013

  • Lin, Philana Ling; Ford, Christopher B.; Coleman, M. Teresa
  • Nature Medicine, Vol. 20, Issue 1
  • DOI: 10.1038/nm.3412

Control of nitric oxide synthase expression by transforming growth factor-β: Implications for homeostasis
journal, January 1994


T Cell-Produced Transforming Growth Factor-β1 Controls T Cell Tolerance and Regulates Th1- and Th17-Cell Differentiation
journal, May 2007


Computational Modeling of Granuloma Formation in Tuberculosis Yields Insights into both Infection and Treatment
journal, January 2014

  • Cilfone, Nicholas A.; Pienaar, Elsje; Kirschner, Denise E.
  • Biophysical Journal, Vol. 106, Issue 2
  • DOI: 10.1016/j.bpj.2013.11.3565

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

The balance between protective and pathogenic immune responses in the TB-infected lung
journal, December 2014

  • Orme, Ian M.; Robinson, Richard T.; Cooper, Andrea M.
  • Nature Immunology, Vol. 16, Issue 1
  • DOI: 10.1038/ni.3048

I NTERLEUKIN -10 AND THE I NTERLEUKIN -10 R ECEPTOR
journal, April 2001


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


A multifaceted approach to modeling the immune response in tuberculosis: Modeling immune response to TB
journal, December 2010

  • Marino, Simeone; Linderman, Jennifer J.; Kirschner, Denise E.
  • Wiley Interdisciplinary Reviews: Systems Biology and Medicine, Vol. 3, Issue 4
  • DOI: 10.1002/wsbm.131

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

Active transforming growth factor-β is associated with phenotypic changes in granulomas after drug treatment in pulmonary tuberculosis
journal, April 2016

  • DiFazio, Robert M.; Mattila, Joshua T.; Klein, Edwin C.
  • Fibrogenesis & Tissue Repair, Vol. 9, Issue 1
  • DOI: 10.1186/s13069-016-0043-3

Identifying mechanisms driving formation of granuloma-associated fibrosis during Mycobacterium tuberculosis infection
journal, September 2017

  • Warsinske, Hayley C.; DiFazio, Robert M.; Linderman, Jennifer J.
  • Journal of Theoretical Biology, Vol. 429
  • DOI: 10.1016/j.jtbi.2017.06.017

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

Regulatory T Cells Reversibly Suppress Cytotoxic T Cell Function Independent of Effector Differentiation
journal, July 2006


A Model to Predict Cell-Mediated Immune Regulatory Mechanisms During Human Infection with Mycobacterium tuberculosis
journal, February 2001


Strategies for Efficient Numerical Implementation of Hybrid Multi-scale Agent-Based Models to Describe Biological Systems
journal, November 2014

  • Cilfone, Nicholas A.; Kirschner, Denise E.; Linderman, Jennifer J.
  • Cellular and Molecular Bioengineering, Vol. 8, Issue 1
  • DOI: 10.1007/s12195-014-0363-6

Computational and Empirical Studies Predict Mycobacterium tuberculosis-Specific T Cells as a Biomarker for Infection Outcome
journal, April 2016


Pirfenidone for the treatment of idiopathic pulmonary fibrosis
journal, November 2013

  • Xaubet, Antoni; Serrano-Mollar, Anna; Ancochea, Julio
  • Expert Opinion on Pharmacotherapy, Vol. 15, Issue 2
  • DOI: 10.1517/14656566.2014.867328

Induction of transforming growth factor beta 1 by purified protein derivative of Mycobacterium tuberculosis.
journal, January 1995


    Works referencing / citing this record:

    Strategies for calibrating models of biology
    journal, September 2018

    • Read, Mark N.; Alden, Kieran; Timmis, Jon
    • Briefings in Bioinformatics
    • DOI: 10.1093/bib/bby092

    Low Levels of T Cell Exhaustion in Tuberculous Lung Granulomas
    journal, June 2018

    • Wong, Eileen A.; Joslyn, Louis; Grant, Nicole L.
    • Infection and Immunity, Vol. 86, Issue 9
    • DOI: 10.1128/iai.00426-18

    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

      Figures/Tables have been extracted from DOE-funded journal article accepted manuscripts.