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J Biol Chem. 2016 Dec 2;291(49):25292-25305. Epub 2016 Oct 5.

Pre-T Cell Receptors (Pre-TCRs) Leverage Vβ Complementarity Determining Regions (CDRs) and Hydrophobic Patch in Mechanosensing Thymic Self-ligands.

Author information

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

Abstract

The pre-T cell receptor (pre-TCR) is a pTα-β heterodimer functioning in early αβ T cell development. Although once thought to be ligand-autonomous, recent studies show that pre-TCRs participate in thymic repertoire formation through recognition of peptides bound to major histocompatibility molecules (pMHC). Using optical tweezers, we probe pre-TCR bonding with pMHC at the single molecule level. Like the αβTCR, the pre-TCR is a mechanosensor undergoing force-based structural transitions that dynamically enhance bond lifetimes and exploiting allosteric control regulated via the Cβ FG loop region. The pre-TCR structural transitions exhibit greater reversibility than TCRαβ and ordered force-bond lifetime curves. Higher piconewton force requires binding through both complementarity determining region loops and hydrophobic Vβ patch apposition. This patch functions in the pre-TCR as a surrogate Vα domain, fostering ligand promiscuity to favor development of β chains with self-reactivity but is occluded by α subunit replacement of pTα upon αβTCR formation. At the double negative 3 thymocyte stage where the pre-TCR is first expressed, pre-TCR interaction with self-pMHC ligands imparts growth and survival advantages as revealed in thymic stromal cultures, imprinting fundamental self-reactivity in the T cell repertoire. Collectively, our data imply the existence of sequential mechanosensor αβTCR repertoire tuning via the pre-TCR.

KEYWORDS:

allosteric regulation; cell differentiation; cell surface receptor; crystallography; major histocompatibility complex (MHC); mechanobiology; nuclear magnetic resonance (NMR); optical tweezers; pre-T cell receptor; structural transition

PMID:
27707880
PMCID:
PMC5207233
DOI:
10.1074/jbc.M116.752865
[Indexed for MEDLINE]
Free PMC Article

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