Abstract
The αβTCR was recently revealed to function as a mechanoreceptor. That is, it leverages mechanical energy generated during immune surveillance and at the immunological synapse to drive biochemical signaling following ligation by a specific foreign peptide–MHC complex (pMHC). Here, we review the structural features that optimize this transmembrane (TM) receptor for mechanotransduction. Specialized adaptations include (1) the CβFG loop region positioned between Vβ and Cβ domains that allosterically gates both dynamic T cell receptor (TCR)–pMHC bond formation and lifetime; (2) the rigid super β-sheet amalgams of heterodimeric CD3εγ and CD3εδ ectodomain components of the αβTCR complex; (3) the αβTCR subunit connecting peptides linking the extracellular and TM segments, particularly the oxidized CxxC motif in each CD3 heterodimeric subunit that facilitates force transfer through the TM segments and surrounding lipid, impacting cytoplasmic tail conformation; and (4) quaternary changes in the αβTCR complex that accompany pMHC ligation under load. How bioforces foster specific αβTCR-based pMHC discrimination and why dynamic bond formation is a primary basis for kinetic proofreading are discussed. We suggest that the details of the molecular rearrangements of individual αβTCR subunit components can be analyzed utilizing a combination of structural biology, single-molecule FRET, optical tweezers, and nanobiology, guided by insightful atomistic molecular dynamic studies. Finally, we review very recent data showing that the pre-TCR complex employs a similar mechanobiology to that of the αβTCR to interact with self-pMHC ligands, impacting early thymic repertoire selection prior to the CD4+CD8+ double positive thymocyte stage of development.
Highlights
Introduction to αβ T Cell ImmunityPrecursors of T and B lymphocytes generate a repertoire of antigen-specific T cell receptors (TCRs) and B cell receptors (BCRs) of immense diversity utilizing somatic rearrangements of variable gene segments (VDJ and VJ recombination) in mammals and other jawed vertebrates
We review very recent data showing that the pre-T cell receptor (pre-TCR) complex employs a similar mechanobiology to that of the αβTCR to interact with self-peptide–MHC complex (pMHC) ligands, impacting early thymic repertoire selection prior to the CD4+CD8+ double positive thymocyte stage of development
Once a T lymphocyte recognizes a variant peptide via its TCR, for example, a foreign peptide derived from a viral proteome bound to a self-major histocompatibility complex (MHC) molecule, signaling is initiated for cytotoxic T lymphocytes (CTL) to kill such a “flagged” cell
Summary
Precursors of T (thymus-derived) and B (bone marrow-derived) lymphocytes generate a repertoire of antigen-specific T cell receptors (TCRs) and B cell receptors (BCRs) of immense diversity utilizing somatic rearrangements of variable gene segments (VDJ and VJ recombination) in mammals and other jawed vertebrates. The multimeric transmembrane (TM) αβTCR complex is composed of an antigen binding αβ disulfide-linked heterodimer that non-covalently associates with the signal-initiating CD3 subunits (CD3εγ, CD3εδ, and CD3ζζ) [reviewed in Ref. Force-dependent structural transitions revealed by single-molecule experiments described below imply that apposition of TCRαβ with CD3εγ and CDεδ subunit heterodimers may change upon pMHC ligation as suggested by recent structural studies [35], impacting downstream signaling. These transformations include creation or ablation of new docking sites, TM conformational changes and accessibility of ITAMs for tyrosine kinase-mediated phosphorylation. Overlay of pTα-β on the αβTCR complex by β subunit superposition shows that pTα (pink) impinges upon the CD3εγ ectodomain (dotted rectangle) while requiring repositioning
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