The Molecular Basis for Recognition of CD1d/α-Galactosylceramide by a Human Non-Vα24 T Cell Receptor

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. © 2012 lópez-sagaseta et al.