The molecular basis for recognition of CD1d/?-galactosylceramide by a human non-V?24 T cell receptor.

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 V?24-J?18 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 TCR? chain rearrangements. Here we present crystallographic and biophysical analyses of ?-galactosylceramide (?-GalCer) recognition by a human CD1d-restricted TCR that utilizes a V?3.1-J?18 rearrangement and displays a more restricted specificity for ?-linked glycolipids than that of iNKT TCRs. Despite having sequence divergence in the CDR1? and CDR2? loops, this TCR employs a convergent recognition strategy to engage CD1d/?GalCer, with a binding affinity (?2 µM) almost identical to that of an iNKT TCR used in this study. The CDR3? loop, similar in sequence to iNKT-TCRs, engages CD1d/?GalCer in a similar position as that seen with iNKT-TCRs, however fewer actual contacts are made. Instead, the CDR1? loop contributes important contacts to CD1d/?GalCer, with an emphasis on the 4'OH of the galactose headgroup. This is consistent with the inability of V?24- T cells to respond to ?-glucosylceramide, which differs from ?GalCer in the position of the 4'OH. These data illustrate how fine specificity for a lipid containing ?-linked galactose is achieved by a TCR structurally distinct from that of iNKT cells.

SUBMITTER: Lopez-Sagaseta J 

PROVIDER: S-EPMC3479090 | biostudies-literature | 2012

REPOSITORIES: biostudies-literature