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BIOMD0000000215 - Schulz2009_Th1_differentiation

 

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Reference Publication
Publication ID: 19409816
Schulz EG, Mariani L, Radbruch A, Höfer T.
Sequential polarization and imprinting of type 1 T helper lymphocytes by interferon-gamma and interleukin-12.
Immunity 2009 May; 30(5): 673-683
Theoretical Biophysics, Institute of Biology, Humboldt Universität, Invalidenstrasse 42, 10115 Berlin, Germany.  [more]
Model
Original Model: BIOMD0000000215.origin
Submitter: Edda Schulz
Submission ID: MODEL9284712021
Submission Date: 10 Jun 2009 14:32:34 UTC
Last Modification Date: 08 Sep 2011 12:14:34 UTC
Creation Date: 10 Jun 2009 14:32:34 UTC
Encoders:  Vijayalakshmi Chelliah
   Edda Schulz
set #1
bqbiol:occursIn Taxonomy Mus musculus
set #2
bqbiol:isVersionOf Gene Ontology T cell differentiation
Notes

This a model from the article:
Sequential polarization and imprinting of type 1 T helper lymphocytes by interferon-gamma and interleukin-12.
Schulz EG, Mariani L, Radbruch A, Höfer T. Immunity. 2009;30(5):666-8. 19409816 ,
Abstract:
Differentiation of naive T lymphocytes into type I T helper (Th1) cells requires interferon-gamma and interleukin-12. It is puzzling that interferon-gamma induces the Th1 transcription factor T-bet, whereas interleukin-12 mediates Th1 cell lineage differentiation. We use mathematical modeling to analyze the expression kinetics of T-bet, interferon-gamma, and the IL-12 receptor beta2 chain (IL-12Rbeta2) during Th1 cell differentiation, in the presence or absence of interleukin-12 or interferon-gamma signaling. We show that interferon-gamma induced initial T-bet expression, whereas IL-12Rbeta2 was repressed by T cell receptor (TCR) signaling. The termination of TCR signaling permitted upregulation of IL-12Rbeta2 by T-bet and interleukin-12 signaling that maintained T-bet expression. This late expression of T-bet, accompanied by the upregulation of the transcription factors Runx3 and Hlx, was required to imprint the Th cell for interferon-gamma re-expression. Thus initial polarization and subsequent imprinting of Th1 cells are mediated by interlinked, sequentially acting positive feedback loops of TCR-interferon-gamma-Stat1-T-bet and interleukin-12-Stat4-T-bet signaling.


The original model was created by:
Edda G. Schulz
schulz@drfz.de
Theoretical Biophysics, Institute of Biology, Humboldt Universität, Invalidenstrasse 42, 10115 Berlin, Germany.

This model originates from BioModels Database: A Database of Annotated Published Models. It is copyright (c) 2005-2009 The BioModels Team.
For more information see the terms of use .
To cite BioModels Database, please use Le Novère N., Bornstein B., Broicher A., Courtot M., Donizelli M., Dharuri H., Li L., Sauro H., Schilstra M., Shapiro B., Snoep J.L., Hucka M. (2006) BioModels Database: A Free, Centralized Database of Curated, Published, Quantitative Kinetic Models of Biochemical and Cellular Systems Nucleic Acids Res., 34: D689-D691.

Model
Publication ID: 19409816 Submission Date: 10 Jun 2009 14:32:34 UTC Last Modification Date: 08 Sep 2011 12:14:34 UTC Creation Date: 10 Jun 2009 14:32:34 UTC
Mathematical expressions
Reactions
Tbet IFN dependend transcription Tbet Receptor dependent transcription Tbet basal expression Tbet mRNA degradation
Tbet protein degradation Rec_mRNA degradation Rec_Prot degradation IFN_mRNA degradation
IFN_Prot degradation Tbet Translation IFN tranlation Rec translation
Rec Transcription IFN transcription    
Rules
Assignment Rule (variable: Ag)      
Physical entities
Compartments Species
compartment Tbet_mRNA Ifn_mRNA Ag
Ifn_Prot Rec_Prot Tbet_Prot
Rec_mRNA    
Reactions (14)
 
 Tbet IFN dependend transcription  → [Tbet_mRNA];   {Ag} , {Ifn_Prot}
 
 Tbet Receptor dependent transcription  → [Tbet_mRNA];   {Rec_Prot}
 
 Tbet basal expression  → [Tbet_mRNA];  
 
 Tbet mRNA degradation [Tbet_mRNA] → ;  
 
 Tbet protein degradation [Tbet_Prot] → ;  
 
 Rec_mRNA degradation [Rec_mRNA] → ;  
 
 Rec_Prot degradation [Rec_Prot] → ;  
 
 IFN_mRNA degradation [Ifn_mRNA] → ;  
 
 IFN_Prot degradation [Ifn_Prot] → ;  
 
 Tbet Translation  → [Tbet_Prot];   {Tbet_mRNA}
 
 IFN tranlation  → [Ifn_Prot];   {Ifn_mRNA}
 
 Rec translation  → [Rec_Prot];   {Rec_mRNA}
 
 Rec Transcription  → [Rec_mRNA];   {Tbet_Prot} , {Ag}
 
 IFN transcription  → [Ifn_mRNA];   {Tbet_Prot} , {Rec_Prot} , {Ag}
 
Rules (1)
 
 Assignment Rule (name: Ag) Ag = 1-time^10/(34^10+time^10)
 
Functions (6)
 
 Rate Law for Tbet IFNg dependent transcription lambda(Ag, K1, Ifn_Prot, K2, a2, a2*Ag/(K1+Ag)*Ifn_Prot/(K2+Ifn_Prot))
 
 Rate Law for Tbet basal expression lambda(a1, a1)
 
 Rate Law for Rec dependent transcription of TBet lambda(a3, Rec_Prot, a3*Rec_Prot)
 
 Translation rate law lambda(b, mRNA, b*mRNA)
 
 Rate Law for Rec Transcription lambda(a4, Tbet_Prot, K4, Ag, a4*Tbet_Prot*K4/(K4+Ag))
 
 Rate Law for IFN transcription lambda(a5, Tbet_Prot, K5, Rec_Prot, K6, Ag, K7, a5*Tbet_Prot/(K5+Tbet_Prot)*Rec_Prot/(K6+Rec_Prot)*Ag/(K7+Ag))
 
 compartment Spatial dimensions: 3.0  Compartment size: 1.0
 
 Tbet_mRNA
Compartment: compartment
Initial concentration: 0.0440000000000001
 
 Ifn_mRNA
Compartment: compartment
Initial concentration: 0.0
 
  Ag
Compartment: compartment
Initial concentration: 1.0
 
 Ifn_Prot
Compartment: compartment
Initial concentration: 0.0
 
 Rec_Prot
Compartment: compartment
Initial concentration: 0.0
 
 Tbet_Prot
Compartment: compartment
Initial concentration: 44.0000000000001
 
 Rec_mRNA
Compartment: compartment
Initial concentration: 0.0
 
Tbet IFN dependend transcription (3)
 
 K1
Value: 0.46
Constant
 
 K2
Value: 2.1
Constant
 
 a2
Value: 0.42
Constant
 
Tbet Receptor dependent transcription (1)
 
   a3
Value: 5.1E-4
Constant
 
Tbet basal expression (1)
 
   a1
Value: 0.044
Constant
 
Tbet mRNA degradation (1)
 
   gamma_Tbet
Value: 1.0
Constant
 
Tbet protein degradation (1)
 
   delta_Tbet
Value: 0.1
Constant
 
Rec_mRNA degradation (1)
 
   gamma_Rec
Value: 1.0
Constant
 
Rec_Prot degradation (1)
 
   delta_Rec
Value: 0.1
Constant
 
IFN_mRNA degradation (1)
 
   gamma_IFN
Value: 1.0
Constant
 
IFN_Prot degradation (1)
 
   delta_IFN
Value: 1.0
Constant
 
Tbet Translation (1)
 
   b
Value: 100.0
Constant
 
IFN tranlation (1)
 
   b
Value: 100.0
Constant
 
Rec translation (1)
 
   b
Value: 100.0
Constant
 
Rec Transcription (2)
 
   a4
Value: 0.0028
Constant
 
   K4
Value: 0.013
Constant
 
IFN transcription (4)
 
   a5
Value: 3.7
Constant
 
   K5
Value: 0.029
Constant
 
   K6
Value: 66.0
Constant
 
   K7
Value: 0.014
Constant
 
Representative curation result(s)
Representative curation result(s) of BIOMD0000000215

Curator's comment: (updated: 11 Jun 2009 14:07:12 BST)

This model represents the two-loop model, which explains the expression kinetics of T-Bet, IL-12Rbeta2 and IFN-gamma during Th1 Cell Priming. Figure 3D of the reference publication (Immunity. 2009 May;30(5):666-8.) is reproduced. Time course simulations are done using Copasi v4.5.

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