PT - JOURNAL ARTICLE AU - Dushek, Omer AU - Aleksic, Milos AU - Wheeler, Richard J. AU - Zhang, Hao AU - Cordoba, Shaun-Paul AU - Peng, Yan-Chun AU - Chen, Ji-Li AU - Cerundolo, Vincenzo AU - Dong, Tao AU - Coombs, Daniel AU - van der Merwe, Philip Anton TI - Antigen Potency and Maximal Efficacy Reveal a Mechanism of Efficient T Cell Activation AID - 10.1126/scisignal.2001430 DP - 2011 Jun 07 TA - Science Signaling PG - ra39--ra39 VI - 4 IP - 176 4099 - http://stke.sciencemag.org/content/4/176/ra39.short 4100 - http://stke.sciencemag.org/content/4/176/ra39.full SO - Sci. Signal.2011 Jun 07; 4 AB - 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).