Mathematical modeling identifies Lck as a potential mediator for PD-1 induced inhibition of early TCR signaling.
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...
| Main Authors: | , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
Public Library of Science (PLoS)
2018-01-01
|
| Series: | PLoS ONE |
| Online Access: | http://europepmc.org/articles/PMC6200280?pdf=render |
| _version_ | 1819038600447131648 |
|---|---|
| author | Theinmozhi Arulraj Debashis Barik |
| author_facet | Theinmozhi Arulraj Debashis Barik |
| author_sort | Theinmozhi Arulraj |
| collection | DOAJ |
| description | 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. |
| first_indexed | 2024-12-21T08:39:53Z |
| format | Article |
| id | doaj.art-980cd72c76b54146852d9b8bdf026f42 |
| institution | Directory Open Access Journal |
| issn | 1932-6203 |
| language | English |
| last_indexed | 2024-12-21T08:39:53Z |
| publishDate | 2018-01-01 |
| publisher | Public Library of Science (PLoS) |
| record_format | Article |
| series | PLoS ONE |
| spelling | doaj.art-980cd72c76b54146852d9b8bdf026f422022-12-21T19:09:58ZengPublic Library of Science (PLoS)PLoS ONE1932-62032018-01-011310e020623210.1371/journal.pone.0206232Mathematical modeling identifies Lck as a potential mediator for PD-1 induced inhibition of early TCR signaling.Theinmozhi ArulrajDebashis BarikProgrammed 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.http://europepmc.org/articles/PMC6200280?pdf=render |
| spellingShingle | Theinmozhi Arulraj Debashis Barik Mathematical modeling identifies Lck as a potential mediator for PD-1 induced inhibition of early TCR signaling. PLoS ONE |
| title | Mathematical modeling identifies Lck as a potential mediator for PD-1 induced inhibition of early TCR signaling. |
| title_full | Mathematical modeling identifies Lck as a potential mediator for PD-1 induced inhibition of early TCR signaling. |
| title_fullStr | Mathematical modeling identifies Lck as a potential mediator for PD-1 induced inhibition of early TCR signaling. |
| title_full_unstemmed | Mathematical modeling identifies Lck as a potential mediator for PD-1 induced inhibition of early TCR signaling. |
| title_short | Mathematical modeling identifies Lck as a potential mediator for PD-1 induced inhibition of early TCR signaling. |
| title_sort | mathematical modeling identifies lck as a potential mediator for pd 1 induced inhibition of early tcr signaling |
| url | http://europepmc.org/articles/PMC6200280?pdf=render |
| work_keys_str_mv | AT theinmozhiarulraj mathematicalmodelingidentifieslckasapotentialmediatorforpd1inducedinhibitionofearlytcrsignaling AT debashisbarik mathematicalmodelingidentifieslckasapotentialmediatorforpd1inducedinhibitionofearlytcrsignaling |