title: Antigen potency and maximal efficacy reveal a mechanism of efficient T cell activation.
abstract: T cell activation, a critical event in adaptive immune responses, depends on productive interactions between T cell receptors (TCRs) and antigens presented as peptide-bound major histocompatibility complexes (pMHCs). Activated T cells lyse infected cells, secrete cytokines, and perform other effector functions with various efficiencies, which depend on the binding parameters of the TCR-pMHC complex. The mechanism through which binding parameters are translated to the efficiency of T cell activation, however, remains controversial. The "affinity model" suggests that the dissociation constant (KD) of the TCR-pMHC complex determines the response, whereas the "productive hit rate model" suggests that the off-rate (koff) is critical. Here, we used mathematical modeling to show that antigen potency, as determined by the EC50 (half-maximal effective concentration), which is used to support KD-based models, could not discriminate between the affinity and the productive hit rate models. Both models predicted a correlation between EC50 and KD, but only the productive hit rate model predicted a correlation between maximal efficacy (Emax), the maximal T cell response induced by pMHC, and koff. We confirmed the predictions made by the productive hit rate model in experiments with cytotoxic T cell clones and a panel of pMHC variants. Thus, we propose that the activity of an antigen is determined by both its potency (EC50) and maximal efficacy (Emax).
authors.affiliation: Sir William Dunn School of Pathology, University of Oxford, OX1 3RE, UK.|Centre for Mathematical Biology, University of Oxford, OX1 3LB, UK.
authors.forename: Omer
authors.initials: O
authors.lastname: Dushek
authors.affiliation: Sir William Dunn School of Pathology, University of Oxford, OX1 3RE, UK.
authors.forename: Milos
authors.initials: M
authors.lastname: Aleksic
authors.affiliation: Sir William Dunn School of Pathology, University of Oxford, OX1 3RE, UK.
authors.forename: Richard J
authors.initials: RJ
authors.lastname: Wheeler
authors.affiliation: Sir William Dunn School of Pathology, University of Oxford, OX1 3RE, UK.
authors.forename: Hao
authors.initials: H
authors.lastname: Zhang
authors.affiliation: Sir William Dunn School of Pathology, University of Oxford, OX1 3RE, UK.
authors.forename: Shaun-Paul
authors.initials: SP
authors.lastname: Cordoba
authors.affiliation: Weatherall Institute of Molecular Medicine, University of Oxford, OX3 9DS, UK.
authors.forename: Yan-Chun
authors.initials: YC
authors.lastname: Peng
authors.affiliation: Weatherall Institute of Molecular Medicine, University of Oxford, OX3 9DS, UK.
authors.forename: Ji-Li
authors.initials: JL
authors.lastname: Chen
authors.affiliation: Weatherall Institute of Molecular Medicine, University of Oxford, OX3 9DS, UK.
authors.forename: Vincenzo
authors.initials: V
authors.lastname: Cerundolo
authors.affiliation: Weatherall Institute of Molecular Medicine, University of Oxford, OX3 9DS, UK.
authors.forename: Tao
authors.initials: T
authors.lastname: Dong
authors.affiliation: Department of Mathematics and Institute of Applied Mathematics, University of British Columbia, V6T 1Z2, Canada.
authors.forename: Daniel
authors.initials: D
authors.lastname: Coombs
authors.affiliation: Sir William Dunn School of Pathology, University of Oxford, OX1 3RE, UK.
authors.forename: P Anton
authors.initials: PA
authors.lastname: van der Merwe
mesh_terms: D056704:Adaptive Immunity; D000818:Animals; D000941:Antigens / Q000276:immunology*; D006801:Humans; D008213:Lymphocyte Activation / Q000276:immunology*; D051379:Mice; D008956:Models, Chemical; D013601:T-Lymphocytes / Q000276:immunology*; D013602:T-Lymphocytes, Cytotoxic / Q000276:immunology; D013816:Thermodynamics
chemical_list: D000941:Antigens