Format

Send to

Choose Destination
J Biol Chem. 2016 Apr 22;291(17):9310-21. doi: 10.1074/jbc.M116.722066. Epub 2016 Feb 25.

Characterization of a Putative Receptor Binding Surface on Skint-1, a Critical Determinant of Dendritic Epidermal T Cell Selection.

Author information

1
From the Cancer Immunology and Immunotherapy Centre, Institute of Immunology and Immunotherapy, University of Birmingham, Edgbaston, Birmingham B15 2TT.
2
the School of Biosciences, University of Birmingham, Edgbaston, Birmingham B15 2TT.
3
the Francis Crick Institute, Lincoln's Inn Fields Research Laboratories, London WC2A 3LY, the Peter Gorer Department of Immunobiology, King's College London, London SE1 9RT, United Kingdom.
4
the School of Cancer Sciences, University of Birmingham, Henry Wellcome Building for Biomolecular NMR, Edgbaston, Birmingham B15 2TT, and.
5
From the Cancer Immunology and Immunotherapy Centre, Institute of Immunology and Immunotherapy, University of Birmingham, Edgbaston, Birmingham B15 2TT, b.willcox@bham.ac.uk.

Abstract

Dendritic epidermal T cells (DETC) form a skin-resident γδ T cell population that makes key contributions to cutaneous immune stress surveillance, including non-redundant contributions to protection from cutaneous carcinogens. How DETC become uniquely associated with the epidermis was in large part solved by the identification of Skint-1, the prototypic member of a novel B7-related multigene family. Expressed only by thymic epithelial cells and epidermal keratinocytes, Skint-1 drives specifically the development of DETC progenitors, making it the first clear candidate for a selecting ligand for non-MHC/CD1-restricted T cells. However, the molecular mechanisms underpinning Skint-1 activity are unresolved. Here, we provide evidence that DETC selection requires Skint-1 expression on the surface of thymic epithelial cells, and depends upon specific residues on the CDR3-like loop within the membrane-distal variable domain of Skint-1 (Skint-1 DV). Nuclear magnetic resonance of Skint-1 DV revealed a core tertiary structure conserved across the Skint family, but a highly distinct surface charge distribution, possibly explaining its unique function. Crucially, the CDR3-like loop formed an electrostatically distinct surface, featuring key charged and hydrophobic solvent-exposed residues, at the membrane-distal tip of DV. These results provide the first structural insights into the Skint family, identifying a putative receptor binding surface that directly implicates Skint-1 in receptor-ligand interactions crucial for DETC selection.

KEYWORDS:

T-cell receptor (TCR); immunology; lymphocyte; nuclear magnetic resonance (NMR); stress

PMID:
26917727
PMCID:
PMC4861494
DOI:
10.1074/jbc.M116.722066
[Indexed for MEDLINE]
Free PMC Article

Supplemental Content

Full text links

Icon for HighWire Icon for PubMed Central
Loading ...
Support Center