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Mathematical modeling identifies Lck as a potential mediator for PD-1 induced inhibition of early TCR signaling

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  • Theinmozhi Arulraj
  • Debashis Barik

Abstract

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.

Suggested Citation

  • Theinmozhi Arulraj & Debashis Barik, 2018. "Mathematical modeling identifies Lck as a potential mediator for PD-1 induced inhibition of early TCR signaling," PLOS ONE, Public Library of Science, vol. 13(10), pages 1-23, October.
  • Handle: RePEc:plo:pone00:0206232
    DOI: 10.1371/journal.pone.0206232
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    1. Nikolaos Patsoukis & Kankana Bardhan & Pranam Chatterjee & Duygu Sari & Bianling Liu & Lauren N. Bell & Edward D. Karoly & Gordon J. Freeman & Victoria Petkova & Pankaj Seth & Lequn Li & Vassiliki A. , 2015. "PD-1 alters T-cell metabolic reprogramming by inhibiting glycolysis and promoting lipolysis and fatty acid oxidation," Nature Communications, Nature, vol. 6(1), pages 1-13, November.
    2. Attila Becskei & Luis Serrano, 2000. "Engineering stability in gene networks by autoregulation," Nature, Nature, vol. 405(6786), pages 590-593, June.
    3. Tian Hong & Jianhua Xing & Liwu Li & John J Tyson, 2011. "A Mathematical Model for the Reciprocal Differentiation of T Helper 17 Cells and Induced Regulatory T Cells," PLOS Computational Biology, Public Library of Science, vol. 7(7), pages 1-13, July.
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