The αβTCR mechanosensor exploits dynamic ectodomain allostery to optimize its ligand recognition site

Each α β T cell receptor (TCR) functions as a mechanosensor. The TCR is comprised of a clonotypic TCR α β ligand-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 TCR α β has 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 TCR α β -pMHC complex and its variants under physiologic loads to identify this mechanism and any attendant TCR α β domain allostery. The TCR α β -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 TCR α β domains and with a pMHC ligand. Applied load enhances fit through deformation of the TCR α β molecule. Thus, the catch bond involves the entire TCR α β conformation, 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 TCR α β ectodomain is structurally conserved, the proposed mechanism can be universally adopted to operate under load during immune surveillance by diverse α β TCRs constituting the T cell repertoire.