Building on earlier work showing that separating force applied to the TCR-peptide-MHC I complex counterintuitively strengthened interactions for T cell stimulating agonist peptides, Wu et al. explored the detailed dynamic interactions using simulations and biophysical assays. A stronger peptide-TCR interface with agonist peptides allowed separating forces to induce new interactions between MHC and TCR domains, which were further strengthened as the MHCα domain separated from β2-microglobulin. These dynamic changes may help explain the impact of HLA polymorphisms and cancer-associated mutations on TCR antigen recognition.
TCRs recognize cognate pMHCs to initiate T cell signaling and adaptive immunity. Mechanical force strengthens TCR-pMHC interactions to elicit agonist-specific catch bonds to trigger TCR signaling, but the underlying dynamic structural mechanism is unclear. We combined steered molecular dynamics (SMD) simulation, single-molecule biophysical approaches, and functional assays to collectively demonstrate that mechanical force induces conformational changes in pMHCs to enhance pre-existing contacts and activates new interactions at the TCR-pMHC binding interface to resist bond dissociation under force, resulting in TCR-pMHC catch bonds and T cell activation. Intriguingly, cancer-associated somatic mutations in HLA-A2 that may restrict these conformational changes suppressed TCR-pMHC catch bonds. Structural analysis also indicated that HLA polymorphism might alter the equilibrium of these conformational changes. Our findings not only reveal critical roles of force-induced conformational changes in pMHCs for activating TCR-pMHC catch bonds but also have implications for T cell-based immunotherapy.