Centre for Systems Biology, School of Life Sciences, University of Hyderabad, Central University P.O., Hyderabad, Telangana, India.
School of Chemistry, University of Hyderabad, Central University P.O., Hyderabad, Telangana, India.
PLoS One. 2018 Oct 24;13(10):e0206232. doi: 10.1371/journal.pone.0206232. eCollection 2018.
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.
程序性细胞死亡蛋白 1（PD-1）是一种抑制性免疫检查点受体，可负向调节 T 细胞的功能。尽管 PD-1 的直接靶标尚未确定，但人们早已知道其对 TCR 信号通路的抑制作用。最近的实验表明，PD-1 在非常早期的阶段（在 TCR 和 CD28 受体胞质结构域磷酸化水平上）抑制 TCR 和 CD28 信号通路。在这里，我们开发了一个数学模型来研究 PD-1 对早期 TCR 和 CD28 信号分子激活的抑制作用的影响。所提出的模型再现了 PD-1 介导的抑制作用的几个定量实验观察。模型模拟表明，PD-1 对 Lck 激酶施加净抑制作用。此外，PD-1 对 TCR 信号分子（如 Zap70 和 SLP76）的激活的抑制作用通过 PD-1 介导的 Lck 抑制显著增强。这些结果表明 Lck 作为 PD-1 诱导的 TCR 信号网络抑制的介质的关键作用。多参数敏感性分析探索了参数不确定性对模型模拟的影响。
