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Sci. Signal., 7 June 2011
Vol. 4, Issue 176, p. ra39
[DOI: 10.1126/scisignal.2001430]


Antigen Potency and Maximal Efficacy Reveal a Mechanism of Efficient T Cell Activation

Omer Dushek1,2*{dagger}, Milos Aleksic1*{ddagger}, Richard J. Wheeler1, Hao Zhang1, Shaun-Paul Cordoba1, Yan-Chun Peng3, Ji-Li Chen3, Vincenzo Cerundolo3, Tao Dong3, Daniel Coombs4, and Philip Anton van der Merwe1{dagger}

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

* These authors contributed equally to this work.

{ddagger} Present address: Immunocore Limited, Abingdon OX14 4RX, UK.

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).

{dagger} To whom correspondence should be addressed. E-mail: omer.dushek{at} (O.D.); anton.vandermerwe{at} (P.A.v.d.M.)

Citation: O. Dushek, M. Aleksic, R. J. Wheeler, H. Zhang, S.-P. Cordoba, Y.-C. Peng, J.-L. Chen, V. Cerundolo, T. Dong, D. Coombs, P. A. van der Merwe, Antigen Potency and Maximal Efficacy Reveal a Mechanism of Efficient T Cell Activation. Sci. Signal. 4, ra39 (2011).

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