Sci. Signal., 7 June 2011
Modeling T Cell ActivationThe efficiency of T cell activation depends on the binding parameters of the interaction between T cell receptors (TCRs) and peptide-bound major histocompatibility complexes (pMHCs). Two models propose different explanations for the relationship between TCR-pMHC binding and T cell functionality. The "affinity model" suggests that the number of TCR-pMHC complexes at equilibrium, which is governed by the dissociation constant KD, is the main determinant, whereas the "productive hit rate model" suggests that T cell responses depend on productive TCR-pMHC interaction times, which depend on the off-rate, koff. Dushek et al. performed mathematical modeling to show that both models predicted a correlation between KD and antigen potency (as measured by the EC50), but that only the productive hit rate model predicted a correlation between the maximal efficiency of antigen-induced responses and koff. Predictions from the productive hit rate model were validated in experiments with T cell clones and a panel of pMHC variants. Improved understanding of TCR-pMHC binding has implications to enhance responsiveness in various immunotherapies.
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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