A Molecular Basis for the Exquisite CD1d-Restricted Antigen Specificity and Functional Responses of Natural Killer T Cells

Abstract

Natural Killer T (NKT) cells respond to a variety of CD1d-restricted antigens (Ags), although the basis for Ag discrimination by the NKT cell receptor (TCR) is unclear. Here we describe NKT TCR fine specificity against several closely related Ags, termed altered glycolipid ligands (AGLs), which differentially stimulate NKT cells. The structures of five ternary complexes all revealed similar docking. Acyl chain modifications did not affect the interaction, but reduced NKT cell proliferation, indicating an affect on Ag processing or presentation. Conversely, truncation of the phytosphingosine chain caused an induced fit mode of TCR binding that affected TCR affinity. Modifications in the glycosyl head group had a direct impact on the TCR interaction and associated cellular response, with ligand potency reflecting the t1/2 life of the interaction. Accordingly, we have provided a molecular basis for understanding how modifications in AGLs can result in striking alterations in the cellular response of NKT cells.

Vβ2 natural killer T cell antigen receptor-mediated recognition of CD1d-glycolipid antigen

“…The Vβ2 NKT TCR adopted a parallel docking mode above the F′ pocket of the CD1d-α-GalCer binding cleft and thus, adopted a docking topology similar to the topology previously observed (14,15,17,18) with the Vβ11, Vβ8.2, and Vβ7 NKT TCRs ( Fig. 2 A-C).…”

“…The α-GalCer analog with a truncated sphingosine chain (OCH) impacted most notably on Vβ2 and Vβ7 NKT TCRs (K d > 6 μM), whereas in comparison, it had a smaller impact on the Vβ8.2 interaction (310 ± 50 nM) ( Fig. 1) (18). Collectively, these results indicate that, although the affinity of the Vβ2 NKT TCR interaction for CD1d-α-GalCer is comparable with the affinity of Vβ8.2 NKT TCRs, both Vβ2 and Vβ7 NKT TCRs are more sensitive to structural modifications of the glycolipid Ag.…”

“…Furthermore, the structures of NKT TCRs in complex with α-GalCer analogs as well as α-galactosyldiacylglycerol, the self-Ag phosphatidyl inositol, and some β-linked Ags have been determined (17)(18)(19)(20)(21)(22)(23). In all NKT TCR-CD1d-Ag complexes determined to date, a conserved, tilted, and parallel docking mode with respect to the CD1d Agbinding cleft was observed.…”

“…In all NKT TCR-CD1d-Ag complexes determined to date, a conserved, tilted, and parallel docking mode with respect to the CD1d Agbinding cleft was observed. Within this common framework, the NKT TCR α-chain dominated the interaction (14,15,17,18,20,22,24). The binding of the human Vβ11 and the mouse Vβ8.2 and Vβ7 chains was largely attributable to the CDR2β-mediated contacts with CD1d.…”

Lipid and Carbohydrate Modifications of α-Galactosylceramide Differently Influence Mouse and Human Type I Natural Killer T Cell Activation

“…TCR Interactions-Previous studies established that the TCR of type I NKT cells binds CD1d with a largely conserved binding footprint (43)(44)(45)(46). Not surprisingly, the contact surfaces between CD1d and the TCR are very similar throughout the different ternary complexes ( Table 2).…”