RT Journal Article
SR Electronic
T1 Antigen Potency and Maximal Efficacy Reveal a Mechanism of Efficient T Cell Activation
JF Science Signaling
JO Sci. Signal.
FD American Association for the Advancement of Science
SP ra39
OP ra39
DO 10.1126/scisignal.2001430
VO 4
IS 176
A1 Dushek, Omer
A1 Aleksic, Milos
A1 Wheeler, Richard J.
A1 Zhang, Hao
A1 Cordoba, Shaun-Paul
A1 Peng, Yan-Chun
A1 Chen, Ji-Li
A1 Cerundolo, Vincenzo
A1 Dong, Tao
A1 Coombs, Daniel
A1 van der Merwe, Philip Anton
YR 2011
UL http://stke.sciencemag.org/content/4/176/ra39.abstract
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).