Carbo2013 - Cytokine driven CD4+ T Cell differentiation and phenotype plasticity

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Carbo2013 - Cytokine driven CD4+ T Cell differentiation and phenotype plasticity

CD4+ T cells can differentiate into different phenotypes depending on the cytokine milieu. Here a computational and mathematical model with sixty ordinary differential equations representing a CD4+ T cell differentiating into either Th1, Th2, Th17 or iTreg cells, has been constructed. The model includes cytokines, nuclear receptors and transcription factors that define fate and function of CD4+ T cells. Computational simulations illustrate how a proinflammatory Th17 cell can undergo reprogramming into an anti-inflammatory iTreg phenotype following PPARc activation.

This model is described in the article:

Carbo A, Hontecillas R, Kronsteiner B, Viladomiu M, Pedragosa M, Lu P, Philipson CW, Hoops S, Marathe M, Eubank S, Bisset K, Wendelsdorf K, Jarrah A, Mei Y, Bassaganya-Riera J
PLoS Computational Biology [2013, 9(4):e1003027]

Abstract:

Differentiation of CD4+ T cells into effector or regulatory phenotypes is tightly controlled by the cytokine milieu, complex intracellular signaling networks and numerous transcriptional regulators. We combined experimental approaches and computational modeling to investigate the mechanisms controlling differentiation and plasticity of CD4+ T cells in the gut of mice. Our computational model encompasses the major intracellular pathways involved in CD4+ T cell differentiation into T helper 1 (Th1), Th2, Th17 and induced regulatory T cells (iTreg). Our modeling efforts predicted a critical role for peroxisome proliferator-activated receptor gamma (PPARγ) in modulating plasticity between Th17 and iTreg cells. PPARγ regulates differentiation, activation and cytokine production, thereby controlling the induction of effector and regulatory responses, and is a promising therapeutic target for dysregulated immune responses and inflammation. Our modeling efforts predict that following PPARγ activation, Th17 cells undergo phenotype switch and become iTreg cells. This prediction was validated by results of adoptive transfer studies showing an increase of colonic iTreg and a decrease of Th17 cells in the gut mucosa of mice with colitis following pharmacological activation of PPARγ. Deletion of PPARγ in CD4+ T cells impaired mucosal iTreg and enhanced colitogenic Th17 responses in mice with CD4+ T cell-induced colitis. Thus, for the first time we provide novel molecular evidence in vivo demonstrating that PPARγ in addition to regulating CD4+ T cell differentiation also plays a major role controlling Th17 and iTreg plasticity in the gut mucosa.

Author's comment: CD4+ T cell computational model (Version 1.4) Steady state corrected. There was a problem in the internalization of IL-17 in its mathematical function.

To the extent possible under law, all copyright and related or neighbouring rights to this encoded model have been dedicated to the public domain worldwide. Please refer to CC0 Public Domain Dedication for more information.

Format
SBML (L2V4)
Related Publication
  • Systems modeling of molecular mechanisms controlling cytokine-driven CD4+ T cell differentiation and phenotype plasticity.
  • Carbo A, Hontecillas R, Kronsteiner B, Viladomiu M, Pedragosa M, Lu P, Philipson CW, Hoops S, Marathe M, Eubank S, Bisset K, Wendelsdorf K, Jarrah A, Mei Y, Bassaganya-Riera J
  • PLoS computational biology , 4/ 2013 , Volume 9 , pages: e1003027
  • Nutritional Immunology and Molecular Medicine Laboratory, Virginia Bioinformatics Institute, Virginia Tech, Blacksburg, Virginia, USA.
  • Differentiation of CD4+ T cells into effector or regulatory phenotypes is tightly controlled by the cytokine milieu, complex intracellular signaling networks and numerous transcriptional regulators. We combined experimental approaches and computational modeling to investigate the mechanisms controlling differentiation and plasticity of CD4+ T cells in the gut of mice. Our computational model encompasses the major intracellular pathways involved in CD4+ T cell differentiation into T helper 1 (Th1), Th2, Th17 and induced regulatory T cells (iTreg). Our modeling efforts predicted a critical role for peroxisome proliferator-activated receptor gamma (PPARγ) in modulating plasticity between Th17 and iTreg cells. PPARγ regulates differentiation, activation and cytokine production, thereby controlling the induction of effector and regulatory responses, and is a promising therapeutic target for dysregulated immune responses and inflammation. Our modeling efforts predict that following PPARγ activation, Th17 cells undergo phenotype switch and become iTreg cells. This prediction was validated by results of adoptive transfer studies showing an increase of colonic iTreg and a decrease of Th17 cells in the gut mucosa of mice with colitis following pharmacological activation of PPARγ. Deletion of PPARγ in CD4+ T cells impaired mucosal iTreg and enhanced colitogenic Th17 responses in mice with CD4+ T cell-induced colitis. Thus, for the first time we provide novel molecular evidence in vivo demonstrating that PPARγ in addition to regulating CD4+ T cell differentiation also plays a major role controlling Th17 and iTreg plasticity in the gut mucosa.
Contributors
Adria Carbo

Metadata information

is
BioModels Database MODEL1304230001
BioModels Database BIOMD0000000451
isDescribedBy
PubMed 23592971
hasTaxon
Taxonomy Mus musculus
isVersionOf
Gene Ontology CD4 biosynthetic process
Gene Ontology T cell differentiation
hasProperty
Mathematical Modelling Ontology Ordinary differential equation model
Human Disease Ontology bacterial infectious disease
occursIn
Brenda Tissue Ontology gut
Curation status
Curated
  • Model originally submitted by : Adria Carbo
  • Submitted: 23-Apr-2013 20:18:47
  • Last Modified: 10-Oct-2014 12:12:39
Revisions
  • Version: 2 public model Download this version
    • Submitted on: 10-Oct-2014 12:12:39
    • Submitted by: Adria Carbo
    • With comment: Current version of Carbo2013 - Cytokine driven CD4+ T Cell differentiation and phenotype plasticity
  • Version: 1 public model Download this version
    • Submitted on: 23-Apr-2013 20:18:47
    • Submitted by: Adria Carbo
    • With comment: Original import of CD4+ T Cell Differentiation model
Curator's comment:
(added: 09 May 2013, 15:36:34, updated: 09 May 2013, 15:36:34)
Figure 3a (Th17 Wild-type) has been reproduced here. The model was simulated using SBML odeSolver. The plots were obtained using Gnuplot.