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

Abstract

T cell activation, a critical event in adaptive immune responses, follows productive interactions between T cell receptors (TCRs) and antigens, in the form of peptide-bound major histocompatibility complexes (pMHCs) on the surfaces of antigen-presenting-cells. Upon activation, T cells can lyse infected cells, secrete cytokines, such as interferon-γ (IFN-γ), and perform other effector functions with various efficiencies that directly depend on the binding parameters of the TCR-pMHC complex. The mechanism that relates binding parameters to the efficiency of activation of the T cell remains controversial; some studies suggest that the dissociation constant (K D ) determines the response (the "affinity model"), whereas others suggest that the off-rate (k off ) is critical (the "productive hit rate model"). Here, we used mathematical modeling to show that antigen potency, as determined by the EC 50 , the functional correlate that is used to support K D -based models, could not be used to discriminate between the affinity and productive hit rate models. Our theoretical work showed that both models predicted a correlation between antigen potency and K D , but only the productive hit rate model predicted a correlation between maximal efficacy (E max ) and k off . We confirmed the predictions made by the productive hit rate model in experiments with cytotoxic T cell clones and a panel of pMHC variants. Therefore, we suggest that the activity of an antigen is determined by both its potency and maximal efficacy. We discuss the implications of our findings to the practical evaluation of T cell activation, for example in adoptive immunotherapies, and relate our work to the pharmacological theory of dose-response. † To whom correspondence should be addressed. omer.dushek@path.ox.ac.uk (O.D.); anton.vandermerwe@path.ox.ac.uk (P.A.V.D.M.) . ‡ Present address: Immunocore Limited, Abingdon, OX14 4RX, UK.

Architecture of a minimal signaling pathway explains the T-cell response to a 1 million-fold variation in antigen affinity and dose

“…First, the dose-response seemed to exhibit a bell shape with reduced cytokine production at high pMHC concentrations. This bell shape was less pronounced or absent for low-affinity ligands, which is consistent with published studies reporting a sigmoidal dose-response for low-affinity ligands (14,15,17,18,21,23,41). Second, the peak amplitude of the bell-shaped dose-response was similar for pMHCs despite large differences in their affinities.…”

“…Studies performed over the last two decades have focused on empirically mapping the relationship between pMHC affinity and T-cell activation (5,(10)(11)(12)(13)(14)(15)(16)(17)(18)(19)(20)(21)(22)(23)(24). A number of studies have reported an optimal pMHC affinity for T-cell activation, but other studies have failed to observe the optimum.…”

Interplay between T Cell Receptor Binding Kinetics and the Level of Cognate Peptide Presented by Major Histocompatibility Complexes Governs CD8+ T Cell Responsiveness

“…5). Our observations are corroborated by mathematical modeling (42,43) demonstrating that, in accordance with the productive hit rate model, as the density of cognate pMHC increases on the surface of an APC, serial triggering becomes less of a determinant of T cell activation for TCR having longer dwell-times. Further, no amount of cognate pMHC can compensate for the reduced T cell responses in the case of TCR having larger k off values (short half-life).…”

Identification of Rare High-Avidity, Tumor-Reactive CD8+ T Cells by Monomeric TCR–Ligand Off-Rates Measurements on Living Cells

“…The stability of TCR binding for the peptide-MHC complex is a key determinant for T-cell activation. Several lines of evidence argue for a close relationship between cell surface dissociation kinetics (k off ) and functional T-cell responses (5,(23)(24)(25)(26)). Yet, rapid and accurate screening methods to measure TCR-pMHC binding kinetics are still needed to isolate antigen-specific T cells expressing TCRs of high binding avidity.…”