Abstract
Type I and type II natural killer T (NKT) cells are restricted to the lipid antigen-presenting molecule CD1d. While we have an understanding of the antigen reactivity and function of type I NKT cells, our knowledge of type II NKT cells in health and disease remains unclear. Here we describe a population of type II NKT cells that recognise and respond to the microbial antigen, α-glucuronosyl-diacylglycerol (α-GlcADAG) presented by CD1d, but not the prototypical type I NKT cell agonist, α-galactosylceramide. Surprisingly, the crystal structure of a type II NKT TCR-CD1d-α-GlcADAG complex reveals a CD1d F’-pocket-docking mode that contrasts sharply with the previously determined A’-roof positioning of a sulfatide-reactive type II NKT TCR. Our data also suggest that diverse type II NKT TCRs directed against distinct microbial or mammalian lipid antigens adopt multiple recognition strategies on CD1d, thereby maximising the potential for type II NKT cells to detect different lipid antigens.
Highlights
Type I and type II natural killer T (NKT) cells are restricted to the lipid antigen-presenting molecule CD1d
We have identified a polyclonal NKT cell population that can recognise the microbial glycolipid α-GlcADAG presented by CD1d
To comprehensively confirm the reactivity of this NKT cell population, we have employed a combination of techniques, including single-cell TCR sequencing, TCR-transduced cell line generation and stimulation, and soluble TCR generation for biophysical and structural analysis
Summary
Type I and type II natural killer T (NKT) cells are restricted to the lipid antigen-presenting molecule CD1d. The most extensively studied are the type I NKT cells, which express an invariant TCR α-chain (Vα14-J18 in mice, Vα24-Jα18 in humans and strongly respond to the glycolipid αgalactosylceramide (α-GalCer)) CD1d restricted, but they are distinguished from type I NKT cells because they neither express the invariant TCR α-chain that characterises type I NKT cells nor do they recognise α-GalCer The availability of α-GalCer and CD1d–α-GalCer tetramers[9] has facilitated the study of type I NKT cells and the development, functional potential, and molecular basis for Ag-recognition by these cells is well understood A limited understanding of the Ags recognised by type II
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