Atomistic basis for the differential load response by the γδ and the chimeric Vγδ-Cαβ T-cell receptors.

αβ and γδ T cells perform vital functions in adaptive and transitional immunity, respectively, and they are both equipped with antigen-sensing T cell receptors. Prototypical recognition of sparse antigenic peptide-loaded major histocompatibility complex molecule (pMHC) by the αβ T-cell receptor (TCRαβ) is assisted by load, through catch bond formation. On the other hand, the contrasting abundance of γδ T cell receptor (TCRγδ) ligands suggests that the recognition may involve a mechanism that is less sensitive to load, as demonstrated in our recent studies. To elucidate structural basis for the load response, we performed a total of 12 µs all-atom molecular dynamics simulations of the 9C2 TCRγδ complexed with the nonclassical MHC molecule CD1d holding a sulfatide lipid antigen JLS (PDB 4LHU). Simulations were performed either without load or with 4.4 to 27.8 pN loads. Contrary to the case of TCRαβ, we did not find any noticeable stabilization of the TCRγδ-CD1d-JLS interface with applied load, supporting an absence of catch bond. We also studied a chimeric Vγδ-Cαβ TCR where the constant domains of PDB 4LHU were replaced with those of N15 TCRαβ (PDB 1NFD). Comparisons between the two systems in terms of interfacial contact dynamics and domain motion reveal how the constant domains can allosterically modulate the interface with the ligand in a load-dependent manner.