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).