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.
Highlights
Activation and subsequent proliferation of T cell are crucial events preceding pathogen clearance
We propose a mathematical model of Programmed cell death-1 (PD-1) pathway that negatively regulates the TCR activation pathway
A key finding of the model is that PD-1-Shp2 complex targets TCR pathway both directly and indirectly
Summary
Activation and subsequent proliferation of T cell are crucial events preceding pathogen clearance. Proper functioning of the immune system relies on the ability of T cells to promote self-tolerance. These processes are tightly controlled at multiple levels by regulatory mechanisms[1]. T cells have co-stimulatory and co-inhibitory receptors that coordinate to modulate its response[2]. Inhibitory receptors CTLA-4 (Cytotoxic T-lymphocyte-associated antigen 4) and PD-1 (Programmed Cell Death-1) negatively regulate the T cell response. Activation of PD-1 receptor has been shown to negatively affect several processes upregulated by the TCR and its associated co-stimulatory signaling pathways[6, 7].Knockouts of the genes encoding these
Sign-in/Register to view highlights & summary Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
