Szomolay, Barbara  ORCID: https://orcid.org/0000-0002-5375-5533 and van den Berg, Hugo A.
2014.
Modulation of T-cell receptor functional sensitivity via the opposing actions of protein tyrosine kinases and phosphatases: a mathematical model.
Integrative Biology
6
(12)
, pp. 1183-1195.
10.1039/C4IB00190G
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Abstract
Combining receptor kinetics and stochastic modelling of receptor activation, we show that a T-cell can specifically augment its functional sensitivity to one particular peptide ligand while simultaneously decreasing its sensitivity to other ligands, by coordinating the expression levels of the co-receptor CD8 and the relative activities of kinases and phosphatases in the vicinity of the T-cell receptor (TCR). We propose that this focusable degeneracy of epitope recognition allows a TCR to have a wide range of potential ligands but be specifically sensitive to only one or a few of these at any one time, which resolves the paradox of how a relatively small number of clones (∼106) can maintain the potential to respond to a vast space of ligands (∼209) whilst avoiding auto-immunity. We validate the model against experimental data and predict shifts in functional sensitivity following a shift in the kinase/phosphatase balance (which could in principle be induced by experimental means). Moreover, we propose that in vivo, the T-cell gauges ligand quality by monitoring changes in TCR triggering rate concomitant with shifts in this balance, for instance as the immunological synapse matures.
| Item Type: | Article |
|---|---|
| Date Type: | Publication |
| Status: | Published |
| Schools: | Schools > Medicine |
| Publisher: | Royal Society of Chemistry |
| ISSN: | 1757-9694 |
| Date of Acceptance: | 4 October 2014 |
| Last Modified: | 23 Oct 2022 13:16 |
| URI: | https://orca.cardiff.ac.uk/id/eprint/110152 |
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