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Proc Natl Acad Sci U S A. 2017 Sep 26;114(39):E8204-E8213. doi: 10.1073/pnas.1703559114. Epub 2017 Aug 15.

Mechanosensing drives acuity of αβ T-cell recognition.

Author information

1
Department of Chemical and Biomolecular Engineering, Vanderbilt University, Nashville, TN 37235.
2
Laboratory of Immunobiology, Dana-Farber Cancer Institute, Boston, MA 02115.
3
Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA 02115.
4
Department of Medicine, Harvard Medical School, Boston, MA 02115.
5
Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, Boston, MA 02115.
6
Laboratory of Immunobiology, Dana-Farber Cancer Institute, Boston, MA 02115; Ellis_Reinherz@dfci.harvard.edu matt.lang@vanderbilt.edu.
7
Department of Chemical and Biomolecular Engineering, Vanderbilt University, Nashville, TN 37235; Ellis_Reinherz@dfci.harvard.edu matt.lang@vanderbilt.edu.
8
Department of Molecular Physiology and Biophysics, Vanderbilt University School of Medicine, Nashville, TN 37235.

Abstract

T lymphocytes use surface [Formula: see text] T-cell receptors (TCRs) to recognize peptides bound to MHC molecules (pMHCs) on antigen-presenting cells (APCs). How the exquisite specificity of high-avidity T cells is achieved is unknown but essential, given the paucity of foreign pMHC ligands relative to the ubiquitous self-pMHC array on an APC. Using optical traps, we determine physicochemical triggering thresholds based on load and force direction. Strikingly, chemical thresholds in the absence of external load require orders of magnitude higher pMHC numbers than observed physiologically. In contrast, force applied in the shear direction ([Formula: see text]10 pN per TCR molecule) triggers T-cell Ca2+ flux with as few as two pMHC molecules at the interacting surface interface with rapid positional relaxation associated with similarly directed motor-dependent transport via [Formula: see text]8-nm steps, behaviors inconsistent with serial engagement during initial TCR triggering. These synergistic directional forces generated during cell motility are essential for adaptive T-cell immunity against infectious pathogens and cancers.

KEYWORDS:

T-cell activation; T-cell receptor; cellular force relaxation; mechanosensor; optical tweezers

Comment in

PMID:
28811364
PMCID:
PMC5625899
DOI:
10.1073/pnas.1703559114
[Indexed for MEDLINE]
Free PMC Article

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