Heterogeneity in mechanical response of αβ T cell receptors

The αβ T-cell receptors (TCRs) are mechanosensors where picoNewton-level forces generated between a T cell and an antigen-presenting cell are utilized for discriminating its ligand, the antigenic peptide-loaded major histocompatibility complex (pMHC) molecules. To elucidate the atomistic basis for mechanical responses, we perform all-atom molecular dynamics simulations where picoNewton shear or tensile loads are applied in several different directions to a set of TCRs recognizing the same NP366/Db pMHC. While those TCRs differ by only 1-3 amino acid residues in their CDR3 loops, they exhibit variegated behaviors in simulations with or without load. In particular, shear forces in certain directions stabilize the interface better compared to cases with tensile or without load. These results suggest that the latch-type binding is a highly sensitive way of directing the load applied to the TCR-pMHC complex into the cytoplasmic signaling modules where different signaling patterns control the activation and differentiation of T cells.