Journal
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
Volume 112, Issue 5, Pages 1517-1522Publisher
NATL ACAD SCIENCES
DOI: 10.1073/pnas.1424829112
Keywords
mechanosensor; T-cell receptor; peptide discrimination; optical tweezers; catch bond
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Funding
- NIH [VSV8/H2-Kb-alpha2A2, R01AI100643, R01AI37581, P01GM047467]
- Vanderbilt-Ingram Cancer Center (NIH) [CA68485]
- Vanderbilt Digestive Disease Research Center (NIH) [DK058404]
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The alpha beta T-cell receptor (TCR) on each T lymphocyte mediates exquisite specificity for a particular foreign peptide bound to a major histocompatibility complex molecule (pMHC) displayed on the surface of altered cells. This recognition stimulates protection in the mammalian host against intracellular pathogens, including viruses, and involves piconewton forces that accompany pMHC ligation. Physical forces are generated by T-lymphocyte movement during immune surveillance as well as by cytoskeletal rearrangements at the immunological synapse following cessation of cell migration. The mechanistic explanation for how TCRs distinguish between foreign and self-peptides bound to a given MHC molecule is unclear: peptide residues themselves comprise few of the TCR contacts on the pMHC, and pathogen-derived peptides are scant among myriad self-peptides bound to the same MHC class arrayed on infected cells. Using optical tweezers and DNA tether spacer technology that permit piconewton force application and nanometer scale precision, we have determined how bioforces relate to self versus nonself discrimination. Single-molecule analyses involving isolated alpha beta-heterodimers as well as complete TCR complexes on T lymphocytes reveal that the FG loop in the beta-subunit constant domain allosterically controls both the variable domain module's catch bond lifetime and peptide discrimination via force-driven conformational transition. In contrast to integrins, the TCR interrogates its ligand via a strong force-loaded state with release through a weakened, extended state. Our work defines a key element of TCR mechanotransduction, explaining why the FG loop structure evolved for adaptive immunity in alpha beta but not gamma delta TCRs or immunoglobulins.
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