The kinetics of two-dimensional TCR and pMHC interactions determine T-cell responsiveness

Abstract

The T cell receptor (TCR) interacts with peptide-major histocompatibility complexes (pMHC) to discriminate pathogens from self-antigens and trigger adaptive immune responses. Direct physical contact is required between the T cell and the antigen-presenting cell (APC) for cross-junctional binding where the TCR and pMHC are anchored on two-dimensional (2D) membranes of the apposing cells1. Despite their 2D nature, TCR-pMHC binding kinetics have only been analyzed three-dimensionally (3D) with a varying degree of correlation with the T cell responsiveness2-4. Here we use two mechanical assays5,6 to show high 2D affinities between a TCR and its antigenic pMHCs driven by rapid on-rates. Compared to their 3D counterparts, 2D affinities and on-rates of the TCR for a panel of pMHC ligands possess far broader dynamic ranges that match that of their corresponding T cell responses. The best 3D predictor of response is the off-rate, with agonist pMHC dissociating the slowest2-4. In contrast, 2D off-rates are up to 8,300-fold faster, with the agonist pMHC dissociating the fastest. Our 2D data suggest rapid antigen sampling by T cells and serial engagement of a few agonist pMHCs by TCRs in a large self pMHC background. Thus, the cellular environment amplifies the TCR-pMHC binding to generate broad affinities and rapid kinetics that determine T-cell responsiveness.

T-cell receptor affinity and avidity defines antitumor response and autoimmunity in T-cell immunotherapy

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Therapeutic enzyme deimmunization by combinatorial T-cell epitope removal using neutral drift

“…In contrast, although mutagenesis of the M 115 RPSTSMSA region resulted in a sequence with improved CPR score with respect to binding DRB1*0401, no statistical difference in cytokine stimulation could be observed for the mutant peptide. This result was probably a consequence of the complex relationship between antigen processing, MHC-II binding, and TCR recognition and signaling (47). Interestingly, although the cytokine responses induced by the 17 N-terminal overlapping peptides were essentially indistinguishable (p ¼ 0.182) regardless of whether the mice had been immunized with WT or mutant enzyme, a significantly reduced response (p < 0.0001) was observed for the 3.1.E2-immunized population across the 15 C-terminal overlapping peptides.…”

The Case for Absolute Ligand Discrimination: Modeling Information Processing and Decision by Immune T Cells

“…Such technique relies on micropipette manipulation of pMHC-coated beads and exquisite measurement of the force induced by the engagement with one individual TCR on the surface of T cells to resolve the dynamics of ligand-receptor engagement. Zhu et al's measurements lead to paradoxical results at first: strong ligands that trigger T cells were found to be weaker binder to the receptor, thus inverting the life-time dogma [33]. Subsequent studies tested how force loading on the ligand-receptor complex would alter its lifetime, and the more intuitive hierarchy of ligands was recovered, with better binders inducing better signaling responses [44].…”