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¹ The Protein Crystallography Unit, Australian Research Council Centre of Excellence in Structural and Functional Microbial Genomics, Department of Biochemistry and Molecular Biology, School of Biomedical Sciences, Monash University, Clayton, Victoria 3800, Australia
² Department of Microbiology and Immunology, University of Melbourne, Parkville, Victoria 3010, Australia
³ Department of Chemistry, University of Connecticut, Storrs, CT 06269
⁴ Department of Immunology, University of Colorado Health Science Center and National Jewish Medical and Research Center, Denver, CO 80206

CORRESPONDENCE Jamie Rossjohn: jamie.rossjohn{at}med.monash.edu.au OR James McCluskey: jamesm1{at}unimelb.edu.au

Although it has been established how CD1 binds a variety of lipid antigens (Ag), data are only now emerging that show how β T cell receptors (TCRs) interact with CD1-Ag. Using the structure of the human semiinvariant NKT TCR–CD1d–-galactosylceramide (-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 -GalCer affected this interaction. The data revealed that an identical energetic footprint underpinned the human and mouse NKT TCR–CD1d–-GalCer cross-reactivity. Some, but not all, of the contact residues within the J18-encoded invariant CDR3 loop and Vβ11-encoded CDR2β loop were critical for recognizing CD1d. The residues within the V24-encoded CDR1 and CDR3 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–-GalCer is small, the energetic footprint is smaller still, and reveals the minimal requirements for CD1d restriction.

Abbreviations used: -GalCer, -galactosylceramide; Ag, antigen; pMHC, peptide-MHC; vdw, van der Waals.

K.S. Wun and N.A. Borg contributed equally to this paper.

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