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

Mahboob Salim, Tim J. Knowles, Rosie Hart, Fiyaz Mohammed, Martin J Woodward, Carrie R. Willcox, Michael Overduin, Adrian C Hayday, Benjamin Willcox

Research output: Contribution to journalArticlepeer-review

13 Citations (Scopus)
142 Downloads (Pure)

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.
Original languageEnglish
Pages (from-to)9310-9321
Number of pages12
JournalJournal of Biological Chemistry
Volume291
Issue number17
Early online date25 Feb 2016
DOIs
Publication statusPublished - 22 Apr 2016

Keywords

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

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