EachαβT cell receptor (TCR) functions as a mechanosensor. The TCR is comprised of a clonotypic TCRαβligand-binding heterodimer and the noncovalently associated CD3 signaling subunits. When bound by ligand, an antigenic peptide arrayed by a major histocompatibility complex molecule (pMHC), the TCRαβhas a longer bond lifetime under piconewton-level loads. The atomistic mechanism of this “catch bond” behavior is unknown. Here, we perform molecular dynamics simulation of a TCRαβ-pMHC complex and its variants under physiologic loads to identify this mechanism and any attendant TCRαβdomain allostery. The TCRαβ-pMHC interface is dynamically maintained by contacts with a spectrum of occupancies, introducing a level of control via relative motion between Vα and Vβ variable domains containing the pMHC-binding complementarity-determining region (CDR) loops. Without adequate load, the interfacial contacts are unstable, whereas applying sufficient load suppresses Vα-Vβ motion, stabilizing the interface. A second level of control is exerted by Cα and Cβ constant domains, especially Cβ and its protruding FG-loop, that create mismatching interfaces among the four TCRαβdomains and with a pMHC ligand. Applied load enhances fit through deformation of the TCRαβmolecule. Thus, the catch bond involves the entire TCRαβconformation, interdomain motion, and interfacial contact dynamics, collectively. This multilayered architecture of the machinery fosters fine-tuning of cellular response to load and pMHC recognition. Since the germline-derived TCRαβectodomain is structurally conserved, the proposed mechanism can be universally adopted to operate under load during immune surveillance by diverseαβTCRs constituting the T cell repertoire.
TheαβTCR mechanosensor exploits dynamic ectodomain allostery to optimize its ligand recognition site
