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Proc Natl Acad Sci U S A. 2015 Jul 7;112(27):8373-8. doi: 10.1073/pnas.1504971112. Epub 2015 Jun 8.

Pre-TCR ligand binding impacts thymocyte development before αβTCR expression.

Author information

1
Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, Boston, MA 02115;
2
Coulter Department of Biomedical Engineering, Georgia Institute of Technology, Atlanta, GA 30332;
3
Department of Medical Oncology, Laboratory of Immunobiology, Dana-Farber Cancer Institute, Boston, MA 02115;
4
School of Chemical and Biomolecular Engineering, Georgia Institute of Technology, Atlanta, GA 30332;
5
Department of Medical Oncology, Laboratory of Immunobiology, Dana-Farber Cancer Institute, Boston, MA 02115; Department of Medicine, Harvard Medical School, Boston, MA 02115;
6
Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, Boston, MA 02115; Department of Medical Oncology, Laboratory of Immunobiology, Dana-Farber Cancer Institute, Boston, MA 02115; Department of Pediatrics, Harvard Medical School, Boston, MA 02115.
7
Department of Medical Oncology, Laboratory of Immunobiology, Dana-Farber Cancer Institute, Boston, MA 02115; Department of Medicine, Harvard Medical School, Boston, MA 02115; ellis_reinherz@dfci.harvard.edu.

Abstract

Adaptive cellular immunity requires accurate self- vs. nonself-discrimination to protect against infections and tumorous transformations while at the same time excluding autoimmunity. This vital capability is programmed in the thymus through selection of αβT-cell receptors (αβTCRs) recognizing peptides bound to MHC molecules (pMHC). Here, we show that the pre-TCR (preTCR), a pTα-β heterodimer appearing before αβTCR expression, directs a previously unappreciated initial phase of repertoire selection. Contrasting with the ligand-independent model of preTCR function, we reveal through NMR and bioforce-probe analyses that the β-subunit binds pMHC using Vβ complementarity-determining regions as well as an exposed hydrophobic Vβ patch characteristic of the preTCR. Force-regulated single bonds akin to those of αβTCRs but with more promiscuous ligand specificity trigger calcium flux. Thus, thymic development involves sequential β- and then, αβ-repertoire tuning, whereby preTCR interactions with self pMHC modulate early thymocyte expansion, with implications for β-selection, immunodominant peptide recognition, and germ line-encoded MHC interaction.

KEYWORDS:

NMR spectroscopy; biomembrane force probe; pre–T-cell receptor; repertoire selection; thymic development

PMID:
26056289
PMCID:
PMC4500245
DOI:
10.1073/pnas.1504971112
[Indexed for MEDLINE]
Free PMC Article

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