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

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Model Identifier
BIOMD0000000724
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.
Format
SBML (L2V4)
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 , PubMed ID: 30356330
  • 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.
Contributors
Submitter of the first revision: Krishna Kumar Tiwari
Submitter of this revision: Rahuman Sheriff
Modellers: Rahuman Sheriff, Krishna Kumar Tiwari

Metadata information

is (2 statements)
BioModels Database MODEL1812040008
BioModels Database BIOMD0000000724

isDescribedBy (1 statement)
PubMed 30356330

hasTaxon (1 statement)
Taxonomy Homo sapiens

hasProperty (3 statements)
occursIn (1 statement)
Brenda Tissue Ontology 0000782

isPropertyOf (1 statement)
Mathematical Modelling Ontology Ordinary differential equation model

Curation status
Curated
Tags

Connected external resources

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Name Description Size Actions

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

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

  • Model originally submitted by : Krishna Kumar Tiwari
  • Submitted: Dec 4, 2018 4:51:24 PM
  • Last Modified: Dec 5, 2018 5:55:10 PM
Revisions
  • Version: 5 public model Download this version
    • Submitted on: Dec 5, 2018 5:55:10 PM
    • Submitted by: Rahuman Sheriff
    • With comment: Edited model metadata online.
  • Version: 3 public model Download this version
    • Submitted on: Dec 4, 2018 4:51:24 PM
    • Submitted by: Krishna Kumar Tiwari
    • With comment: Automatically added model identifier BIOMD0000000724

(*) You might be seeing discontinuous revisions as only public revisions are displayed here. Any private revisions unpublished model revision of this model will only be shown to the submitter and their collaborators.

Legends
: Variable used inside SBML models


Species
Species Initial Concentration/Amount
LCKyi

Tyrosine-protein kinase Lck ; 0002355 		25.0 nmol
PD1

Programmed cell death 1 ligand 1 ; 0002355 		500.0 nmol
CD28a

T-cell-specific surface glycoprotein CD28 ; 0002220 		0.0 nmol
LCKya

Tyrosine-protein kinase Lck ; 0002220 		25.0 nmol
PD1p1

Programmed cell death 1 ligand 1 ; 0002220 		0.0 nmol
CP1

Tyrosine-protein phosphatase non-receptor type 11 ; Programmed cell death 1 ligand 1 ; 0002220 		0.0 nmol
PI3Kb

Phosphatidylinositol 3-kinase regulatory subunit alpha ; Phosphatidylinositol 4,5-bisphosphate 3-kinase catalytic subunit alpha isoform ; 0002220 		0.0 nmol
CD3a

T-cell surface glycoprotein CD3 zeta chain ; 0002220 		0.0 nmol
LCKpi

Tyrosine-protein kinase Lck ; 0002220 		0.0 nmol
Reactions
Reactions Rate Parameters
LCKyi => LCKpi Cell*Kpa_yi*LCKyi Kpa_yi = 7.5E-4 1/s
CP1 => SHP2 + PD1 Cell*Kd2_shp*CP1 Kd2_shp = 1.0 1/s
CD28i => CD28a; LCKactive Cell*Kp_cd28*LCKactive*CD28i/(KMp_cd28+CD28i) Kp_cd28 = 1.0 1/s; KMp_cd28 = 1000.0 nmol/l
LCKyiya => LCKya; CPactive Cell*Kdpi_yiya*CPactive*LCKyiya Kdpi_yiya = 0.0 l/(nmol*s)
CP2 => SHP2 + PD1p1 Cell*Kd2_shp*CP2 Kd2_shp = 1.0 1/s
LCKya => LCKyiya Cell*Kpi_ya*LCKya Kpi_ya = 6.0E-5 1/s
CP2 => CP1 Cell*Kdp_cp2*CP2 Kdp_cp2 = 5.0E-8 1/s
CD28a + PI3K => PI3Kb Cell*(Ka_pi3k*CD28a*PI3K-Kd_pi3k*PI3Kb) Ka_pi3k = 1.4E-6 l/(nmol*s); Kd_pi3k = 9.0E-4 1/s
CD3i => CD3a; LCKactive Cell*Kp_cd3*LCKactive*CD3i/(KMp_cd3+CD3i) KMp_cd3 = 80.0 nmol/l; Kp_cd3 = 3.29 1/s
LCKpi => LCKyi; CPactive Cell*Kdpa_pi*CPactive*LCKpi Kdpa_pi = 0.0 l/(nmol*s)
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).