title: The molecular basis for recognition of CD1d/α-galactosylceramide by a human non-Vα24 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 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.
authors.affiliation: Department of Biochemistry and Molecular Biology, University of Chicago, Chicago, Illinois, United States of America.
authors.forename: Jacinto
authors.initials: J
authors.lastname: López-Sagaseta
authors.forename: Jennifer E
authors.initials: JE
authors.lastname: Kung
authors.forename: Paul B
authors.initials: PB
authors.lastname: Savage
authors.forename: Jenny
authors.initials: J
authors.lastname: Gumperz
authors.forename: Erin J
authors.initials: EJ
authors.lastname: Adams
mesh_terms: D000595:Amino Acid Sequence; D017951:Antigen Presentation; D055610:Antigens, CD1d / Q000737:chemistry* / Q000378:metabolism; D001665:Binding Sites; D018360:Crystallography, X-Ray; D005699:Galactosylceramides / Q000737:chemistry* / Q000378:metabolism; D006801:Humans; D008969:Molecular Sequence Data; D055611:Natural Killer T-Cells / Q000378:metabolism; D011948:Receptors, Antigen, T-Cell / Q000737:chemistry / Q000378:metabolism; D001613:beta 2-Microglobulin / Q000737:chemistry / Q000378:metabolism
chemical_list: D055610:Antigens, CD1d; C526877:CD1D protein, human; D005699:Galactosylceramides; D011948:Receptors, Antigen, T-Cell; C528689:Valpha24 protein, human; C493154:alpha-galactosylceramide; D001613:beta 2-Microglobulin