title: The contribution of major histocompatibility complex contacts to the affinity and kinetics of T cell receptor binding.
abstract: The interaction between the T cell antigen receptor (TCR) and antigenic peptide in complex with major histocompatibility complex (MHC) molecules is a crucial step in T cell activation. The relative contributions of TCR:peptide and TCR:MHC contacts to the overall binding energy remain unclear. This has important implications for our understanding of T cell development and function. In this study we used site directed mutagenesis to estimate the contribution of HLA-A2 side-chains to the binding of four TCRs. Our results show that these TCRs have very different energetic 'footprints' on HLA-A2, with no residues contributing to all TCR interactions. The estimated overall contribution of MHC side-chains to the total interaction energy was variable, with lower limits ranging from 11% to 50%. Kinetic analysis suggested a minor and variable contribution of MHC side-chains to the transition state complex, arguing against a two-step mechanism for TCR binding.
authors.affiliation: Sir William Dunn School of Pathology, University of Oxford, United Kingdom.
authors.forename: Hao
authors.initials: H
authors.lastname: Zhang
authors.affiliation: Sir William Dunn School of Pathology, University of Oxford, United Kingdom.
authors.forename: Hong-Sheng
authors.initials: HS
authors.lastname: Lim
authors.affiliation: Department of Statistics, University of Oxford, United Kingdom.
authors.forename: Berhard
authors.initials: B
authors.lastname: Knapp
authors.affiliation: Department of Statistics, University of Oxford, United Kingdom.
authors.forename: Charlotte M
authors.initials: CM
authors.lastname: Deane
authors.affiliation: Sir William Dunn School of Pathology, University of Oxford, United Kingdom.
authors.forename: Milos
authors.initials: M
authors.lastname: Aleksic
authors.affiliation: Sir William Dunn School of Pathology, University of Oxford, United Kingdom.
authors.forename: Omer
authors.initials: O
authors.lastname: Dushek
authors.affiliation: Sir William Dunn School of Pathology, University of Oxford, United Kingdom.
authors.forename: P Anton
authors.initials: PA
authors.lastname: van der Merwe
mesh_terms: D000818:Animals; D000939:Epitopes / Q000737:chemistry; D015789:HLA-A2 Antigen / Q000737:chemistry*; D007700:Kinetics; D008213:Lymphocyte Activation; D008285:Major Histocompatibility Complex; D051379:Mice; D008958:Models, Molecular; D056004:Molecular Dynamics Simulation; D016297:Mutagenesis, Site-Directed; D009154:Mutation; D010455:Peptides / Q000737:chemistry; D011485:Protein Binding; D017433:Protein Structure, Secondary; D011948:Receptors, Antigen, T-Cell / Q000737:chemistry*; D020349:Surface Plasmon Resonance; D013601:T-Lymphocytes / Q000276:immunology*; D013816:Thermodynamics
chemical_list: D000939:Epitopes; D015789:HLA-A2 Antigen; D010455:Peptides; D011948:Receptors, Antigen, T-Cell