Heterogeneity of mechanical responses of αβ T-cell receptors 2257683

Abstract Introduction Alpha beta T cell receptors (TCRs) recognize target ligands, antigenic peptide-loaded major histocompatibility complex molecules (pMHCs). The recognition occurs under variegated physical conditions including distinct local mechanical environments and target ligand densities in the background of self-pMHC molecules. A key TCR feature is mechanosensing, a process whereby picoNewton-level forces applied to the TCRαβ-pMHC complexes during immune surveillance elicit a catch bond response. Our recent computational and experimental studies indicate that TCRs exhibit a diverse range of mechanical behaviors including differences in catch bond profiles and stiffness. The basis of this divergence is yet to be elucidated. Methods We perform all-atom molecular dynamics simulations where picoNewton-level forces are applied to three structures of TCRαβ-pMHC (NP366/Db) complexes bearing an identical peptide from influenza A virus. While those TCRs differ by only 1-3 amino acids in their CDR3 loops, the corresponding T cells selectively differentiate into different CD8 memory cell lineages. In simulations, we apply loads in various ways, including tension, shear, and differential loading on α and β chains, which cover various scenarios of loading on the holo-TCR during immune surveillance. Results Despite the structural similarity of the NP TCRs, we first find that the stability of each TCRαβ-pMHC interface varies without load. Application of shear forces in different directions relative to pMHC reveals that the increase in interfacial stability depends on the loading direction. Conclusion These results indicate that the differences in response to load may control conformational motion of the holo-TCR, leading to distinct signaling outcomes. Funding Source US National Institutes of Health (Grant number P01AI143565) Topic Categories Immune Response Regulation: Molecular Mechanisms (IRM)