Molecular design of the T cell receptor ectodomain encodes biologically fit ligand recognition in the absence of mechanosensing.
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abstract
High-acuity T cell receptor (TCR) recognition of peptides bound to major histocompatibility complex molecules (pMHCs) requires mechanosensing, a process whereby piconewton (pN) bioforces exert physical load on TCR-pMHC bonds to dynamically alter their lifetimes and foster digital sensitivity cellular signaling. While mechanotransduction is operative for both TCRs and pre-TCRs within the T lineage, its role in T cells is unknown. Here, we show that the human DP10.7 TCR specific for the sulfoglycolipid sulfatide bound to CD1d only sustains a significant load and undergoes force-induced structural transitions when the binding interface-distal constant domain (C) module is replaced with that of . The chimeric -TCR also signals more robustly than does the wild-type (WT) TCR, as revealed by RNA-sequencing (RNA-seq) analysis of TCR-transduced Rag2-/- thymocytes, consistent with structural, single-molecule, and molecular dynamics studies reflective of TCRs as mediating recognition via a more canonical immunoglobulin-like receptor interaction. Absence of robust, force-related catch bonds, as well as TCR structural transitions, implies that T cells do not use mechanosensing for ligand recognition. This distinction is consonant with the fact that their innate-type ligands, including markers of cellular stress, are expressed at a high copy number relative to the sparse pMHC ligands of T cells arrayed on activating target cells. We posit that mechanosensing emerged over 200 million years of vertebrate evolution to fulfill indispensable adaptive immune recognition requirements for pMHC in the T cell lineage that are unnecessary for the T cell lineage mechanism of non-pMHC ligand detection.
