A minimal binding footprint on CD1d-glycolipid is a basis for selection of the unique human NKT TCR

Kwok Soon Wun, Natalie Borg, Lars Kjer-Nielsen, Travis Clarke Beddoe, Ruide Koh, Stewart K Richardson, Meena Thakur, Amy R Howell, James P Scott-Browne, Laurent Gapin, Dale I Godfrey, James McCluskey, Jamie Rossjohn

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79 Citations (Scopus)


Although it has been established how CD1 binds a variety of lipid antigens (Ag), data are only now emerging that show how alphabeta T cell receptors (TCRs) interact with CD1-Ag. Using the structure of the human semiinvariant NKT TCR-CD1d-alpha-galactosylceramide (alpha-GalCer) complex as a guide, we undertook an alanine scanning mutagenesis approach to define the energetic basis of this interaction between the NKT TCR and CD1d. Moreover, we explored how analogues of alpha-GalCer affected this interaction. The data revealed that an identical energetic footprint underpinned the human and mouse NKT TCR-CD1d-alpha-GalCer cross-reactivity. Some, but not all, of the contact residues within the Jalpha18-encoded invariant CDR3alpha loop and Vbeta11-encoded CDR2beta loop were critical for recognizing CD1d. The residues within the Valpha24-encoded CDR1alpha and CDR3alpha loops that contacted the glycolipid Ag played a smaller energetic role compared with the NKT TCR residues that contacted CD1d. Collectively, our data reveal that the region distant to the protruding Ag and directly above the F pocket of CD1d was the principal factor in the interaction with the NKT TCR. Accordingly, although the structural footprint at the NKT TCR-CD1d-alpha-GalCer is small, the energetic footprint is smaller still, and reveals the minimal requirements for CD1d restriction.
Original languageEnglish
Pages (from-to)939 - 949
Number of pages11
JournalJournal of Experimental Medicine
Issue number4
Publication statusPublished - 2008

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