title: Modulation of T-cell receptor functional sensitivity via the opposing actions of protein tyrosine kinases and phosphatases: a mathematical model.
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 (∼10(6)) can maintain the potential to respond to a vast space of ligands (∼20(9)) 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.
authors.affiliation: University of Warwick, Coventry CV4 7AL, UK. hugo@maths.warwick.ac.uk.
authors.forename: Barbara
authors.initials: B
authors.lastname: Szomolay
authors.forename: Hugo A
authors.initials: HA
authors.lastname: van den Berg
mesh_terms: D000818:Animals; D001665:Binding Sites; D002478:Cells, Cultured; D003198:Computer Simulation; D006801:Humans; D008956:Models, Chemical; D018448:Models, Immunological; D011485:Protein Binding; D017027:Protein Tyrosine Phosphatases / Q000737:chemistry / Q000276:immunology*; D011505:Protein-Tyrosine Kinases / Q000737:chemistry / Q000276:immunology*; D011948:Receptors, Antigen, T-Cell / Q000737:chemistry / Q000276:immunology*; D013601:T-Lymphocytes / Q000737:chemistry / Q000276:immunology*
chemical_list: D011948:Receptors, Antigen, T-Cell; D011505:Protein-Tyrosine Kinases; D017027:Protein Tyrosine Phosphatases