Differential Recognition of CD1d-α-Galactosyl Ceramide by the Vβ8.2 and Vβ7 Semi-invariant NKT T Cell Receptors

The semi-invariant natural killer T cell receptor (NKT TCR) recognizes CD1d-lipid antigens. Although the TCRα chain is typically invariant, the β chain expression is more diverse, where three Vβ chains are commonly expressed in mice. We report the structures of Vα14-Vβ8.2 and Vα14-Vβ7 NKT TCRs in complex with CD1d-α-galactosylceramide (α-GalCer) and the 2.5 A structure of the human NKT TCR-CD1d-α-GalCer complex. Both Vβ8.2 and Vβ7 NKT TCRs and the human NKT TCR ligated CD1d-α-GalCer in a similar manner, highlighting the evolutionarily conserved interaction. However, differences within the Vβ domains of the Vβ8.2 and Vβ7 NKT TCR-CD1d complexes resulted in altered TCRβ-CD1d-mediated contacts and modulated recognition mediated by the invariant α chain. Mutagenesis studies revealed the differing contributions of Vβ8.2 and Vβ7 residues within the CDR2β loop in mediating contacts with CD1d. Collectively we provide a structural basis for the differential NKT TCR Vβ usage in NKT cells.