Theinmozhi2018 - Mechanism of PD1 inhibiting TCR signaling in Tumor immune regulation

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Short description
Its a Deterministic ODE model showcasing mechanism of PDL1 induced TCR and CD38 signalling inhibition. The model also contains the LCK activation and inactivation phenomenon dependent on the particular phosphorylation site. This model is relevant in immunotherapy. 
Related Publication
  • Mathematical modeling identifies Lck as a potential mediator for PD-1 induced inhibition of early TCR signaling.
  • Arulraj T, Barik D
  • PloS one , 1/ 2018 , Volume 13 , Issue 10 , pages: e0206232
  • Centre for Systems Biology, School of Life Sciences, University of Hyderabad, Central University P.O., Hyderabad, Telangana, India.
  • Programmed cell death-1 (PD-1) is an inhibitory immune checkpoint receptor that negatively regulates the functioning of T cell. Although the direct targets of PD-1 were not identified, its inhibitory action on the TCR signaling pathway was known much earlier. Recent experiments suggest that the PD-1 inhibits the TCR and CD28 signaling pathways at a very early stage ─ at the level of phosphorylation of the cytoplasmic domain of TCR and CD28 receptors. Here, we develop a mathematical model to investigate the influence of inhibitory effect of PD-1 on the activation of early TCR and CD28 signaling molecules. Proposed model recaptures several quantitative experimental observations of PD-1 mediated inhibition. Model simulations show that PD-1 imposes a net inhibitory effect on the Lck kinase. Further, the inhibitory effect of PD-1 on the activation of TCR signaling molecules such as Zap70 and SLP76 is significantly enhanced by the PD-1 mediated inhibition of Lck. These results suggest a critical role for Lck as a mediator for PD-1 induced inhibition of TCR signaling network. Multi parametric sensitivity analysis explores the effect of parameter uncertainty on model simulations.
Krishna Kumar Tiwari, Rahuman Sheriff

Metadata information

Taxonomy Homo sapiens
Mathematical Modelling Ontology MAMO:0000046
Curation status
Name Description Size Actions

Model files

Theinmozhi_2018.xml SBML Level 2 version 4 180.90 KB Preview | Download

Additional files

Theinmozhi_2018.sedml SEDML file for figure 7C, 7D of reference publication 72.38 KB Preview | Download
Theinmozhi_2018.cps COPASI version 4.23 (Build 184) file for figure 7C, 7D of reference publication. 256.60 KB Preview | Download

  • Model originally submitted by : Krishna Kumar Tiwari
  • Submitted: 04-Dec-2018 16:51:24
  • Last Modified: 05-Dec-2018 17:55:10
  • Version: 5 public model Download this version
    • Submitted on: 05-Dec-2018 17:55:10
    • Submitted by: Rahuman Sheriff
    • With comment: Edited model metadata online.
  • Version: 3 public model Download this version
    • Submitted on: 04-Dec-2018 16:51:24
    • Submitted by: Krishna Kumar Tiwari
    • With comment: Automatically added model identifier BIOMD0000000724
Curator's comment:
(added: 04 Dec 2018, 16:48:34, updated: 04 Dec 2018, 16:48:34)
Figure 2c, 2e, 2f, 7a, 7c and 7d is reproduced from reference publication with the species concentrations described for each figure. Simulation figures are generated using COPASI 4.23 (build184).