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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

1
Sir William Dunn School of Pathology, University of Oxford, OX1 3RE, UK.
2
Centre for Mathematical Biology, University of Oxford, OX1 3LB, UK.
3
Weatherall Institute of Molecular Medicine, University of Oxford, OX3 9DS, UK.
4
Department of Mathematics and Institute of Applied Mathematics, University of British Columbia, V6T 1Z2, Canada.
#
Contributed equally

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).

PMID:
21653229
PMCID:
PMC4143974
DOI:
10.1126/scisignal.2001430
[Indexed for MEDLINE]
Free PMC Article

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