BPS2026 – Loading-direction-dependent responses of alpha beta T cell receptors

Alpha beta T cells recognize target ligands, antigenic peptide-loaded major histocompatibility complex molecules (pMHCs), displayed on antigen-presenting cells (APCs) with exquisite specificity and sensitivity via their alpha beta T cell receptors (TCRs). Underlying high performance TCR function is mechanosensing, a process whereby picoNewton-level forces applied to the TCRab-pMHC complexes during immune surveillance elicit a catch bond response. Depending on the type of TCR and the ligand, a reversible conformational transition may occur that extends the TCRab-pMHC bond lifetime by orders of magnitude, impacting functionality and cellular performance. Furthermore, it appears that different “modes of interaction” foster differentiation into distinct CD8 memory T cell subpopulations even though the corresponding TCRs recognize the same pMHC. To elucidate the basis of this divergence, we perform all-atom molecular dynamics simulations where picoNewton-level forces are applied to three structures of TCRab-pMHC (NP366/Db) complexes bearing an identical peptide from influenza A virus. While those TCRs differ by only 1-3 amino acid residues in their CDR3 loops, the corresponding T cells selectively differentiate into different CD8 memory cell lineages. Strikingly, despite their structural similarity, we find that the stability of the TCRab-pMHC interface without load differs among these systems and that the increase in interfacial stability depends on the direction of load. These results indicate that the differences in response to load may determine the load propagation pathway through the holo-TCR, which in turn leads to distinct signaling outcomes as the altered ectodomain motions divergently affect CD3 cytoplasmic signaling modules and downstream pathways.