title: An induced rebinding model of antigen discrimination.
abstract: T cells have to detect rare high-affinity 'foreign' peptide MHC (pMHC) ligands among abundant low-affinity 'self'-peptide MHC ligands. It remains unclear how this remarkable discrimination is achieved. Kinetic proofreading mechanisms can provide the required specificity but only at the expense of much reduced sensitivity. A number of recent observations suggest that pMHC engagement of T cell receptors (TCRs) induces changes such as clustering and/or conformational alterations that enhance subsequent rebinding. We show that inclusion of induced rebinding to the same pMHC in kinetic proofreading models enhances the sensitivity of TCR recognition while retaining specificity. Moreover, induced rebinding is able to reproduce the striking, and hitherto unexplained, 2D membrane-binding properties recently reported for the TCR.
authors.affiliation: Sir William Dunn School of Pathology, University of Oxford, Oxford, UK; Wolfson Centre for Mathematical Biology, University of Oxford, Oxford, UK. Electronic address: omer.dushek@path.ox.ac.uk.
authors.forename: Omer
authors.initials: O
authors.lastname: Dushek
authors.affiliation: Sir William Dunn School of Pathology, University of Oxford, Oxford, UK. Electronic address: anton.vandermerwe@path.ox.ac.uk.
authors.forename: P Anton
authors.initials: PA
authors.lastname: van der Merwe
mesh_terms: D000818:Animals; D006801:Humans; D008213:Lymphocyte Activation / Q000276:immunology*; D008285:Major Histocompatibility Complex / Q000276:immunology*; D018448:Models, Immunological; D011485:Protein Binding / Q000276:immunology; D011948:Receptors, Antigen, T-Cell / Q000276:immunology*; D017634:Self Tolerance / Q000276:immunology
chemical_list: D011948:Receptors, Antigen, T-Cell