Dynamic allostery of T-cell receptor chassis motion for pMHC discrimination under applied load 2768

Abstract Description Recent experimental advances have shown that αβ T-cell receptors (TCRs) are mechanosensors such that picoNewton-level forces generated between a T-cell and an antigen-presenting cell (APC) activate a catch bond formation with the target pMHC ligand. As the applied load is tuned by the actin cytoskeleton of the T-cell and the APC, the cognate TCR-pMHC complex can subsequently undergo reversible conformational transitions termed volleying, which extends the seconds-long bond lifetime to the order of minutes. We use atomistic molecular dynamics simulation of different TCR-pMHC complexes under various loading conditions to elucidate the underlying mechanisms for this behavior. We find that a conserved motion of the TCRαβ chassis causes the complementarity determining region loops to move relative to each other, where binding with the pMHC can be stabilized only with a cognate peptide and an adequate level of load. These results explain how TCR-pMHC complexes that differ only by point mutations and have very similar crystal structures can nevertheless lead to disparate functional outcomes as they differ in dynamic response to load. We further combine these results with a kinetic model to show how volleying can drastically increase the bond lifetime such that T-cell activation can occur by as little as a single TCR-pMHC interaction. These results have implications in designing T-cell screening modality for adoptive T-cell immunotherapy. Funding Sources Supported by NIH/NIAID AI143565; NIH AI136301 Topic Categories Immune Response Regulation: Molecular Mechanisms (IRM)