The Molecular Basis for Recognition of CD1d/[alpha]-Galactosylceramide by a Human Non-V[alpha]24 T Cell Receptor

• Published in: PLoS biology Vol. 10; no. 10
• Main Authors: López-Sagaseta, Jacinto, Kung, Jennifer E, Savage, Paul B, Gumperz, Jenny, Adams, Erin J
• Format: Journal Article
• Language: English
• Published: San Francisco Public Library of Science 01-10-2012
• Subjects: Immunology; Lipids; Proteins; T cell receptors; Amino Acid Sequence; Galactosylceramides; beta 2-Microglobulin; Antigen Presentation; Antigens, CD1d; Humans; Molecular Sequence Data; Crystallography, X-Ray; Receptors, Antigen, T-Cell; Binding Sites; Natural Killer T-Cells
• ISSN: 1544-9173; 1545-7885
• DOI: 10.1371/journal.pbio.1001412

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.