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Sci Signal. 2011 Jun 7;4(176):ra39. doi: 10.1126/scisignal.2001430.

Antigen potency and maximal efficacy reveal a mechanism of efficient T cell activation.

Author information

Sir William Dunn School of Pathology, University of Oxford, OX1 3RE, UK.
Centre for Mathematical Biology, University of Oxford, OX1 3LB, UK.
Weatherall Institute of Molecular Medicine, University of Oxford, OX3 9DS, UK.
Department of Mathematics and Institute of Applied Mathematics, University of British Columbia, V6T 1Z2, Canada.
Contributed equally


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).

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