The molecular basis for recognition of CD1d/α-galactosylceramide by a human non-Vα24 T cell receptor

PLoS Biol. 2012;10(10):e1001412. doi: 10.1371/journal.pbio.1001412. Epub 2012 Oct 23.

Abstract

CD1d-mediated presentation of glycolipid antigens to T cells is capable of initiating powerful immune responses that can have a beneficial impact on many diseases. Molecular analyses have recently detailed the lipid antigen recognition strategies utilized by the invariant Vα24-Jα18 TCR rearrangements of iNKT cells, which comprise a subset of the human CD1d-restricted T cell population. In contrast, little is known about how lipid antigens are recognized by functionally distinct CD1d-restricted T cells bearing different TCRα chain rearrangements. Here we present crystallographic and biophysical analyses of α-galactosylceramide (α-GalCer) recognition by a human CD1d-restricted TCR that utilizes a Vα3.1-Jα18 rearrangement and displays a more restricted specificity for α-linked glycolipids than that of iNKT TCRs. Despite having sequence divergence in the CDR1α and CDR2α loops, this TCR employs a convergent recognition strategy to engage CD1d/αGalCer, with a binding affinity (∼2 µM) almost identical to that of an iNKT TCR used in this study. The CDR3α loop, similar in sequence to iNKT-TCRs, engages CD1d/αGalCer in a similar position as that seen with iNKT-TCRs, however fewer actual contacts are made. Instead, the CDR1α loop contributes important contacts to CD1d/αGalCer, with an emphasis on the 4'OH of the galactose headgroup. This is consistent with the inability of Vα24- T cells to respond to α-glucosylceramide, which differs from αGalCer in the position of the 4'OH. These data illustrate how fine specificity for a lipid containing α-linked galactose is achieved by a TCR structurally distinct from that of iNKT cells.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Amino Acid Sequence
  • Antigen Presentation
  • Antigens, CD1d / chemistry*
  • Antigens, CD1d / metabolism
  • Binding Sites
  • Crystallography, X-Ray
  • Galactosylceramides / chemistry*
  • Galactosylceramides / metabolism
  • Humans
  • Molecular Sequence Data
  • Natural Killer T-Cells / metabolism
  • Receptors, Antigen, T-Cell / chemistry
  • Receptors, Antigen, T-Cell / metabolism
  • beta 2-Microglobulin / chemistry
  • beta 2-Microglobulin / metabolism

Substances

  • Antigens, CD1d
  • CD1D protein, human
  • Galactosylceramides
  • Receptors, Antigen, T-Cell
  • Valpha24 protein, human
  • alpha-galactosylceramide
  • beta 2-Microglobulin