Antigen Specificity of Type I NKT Cells Is Governed by TCR ß-Chain Diversity.

NKT cells recognize lipid-based Ags presented by CD1d. Type I NKT cells are often referred to as invariant owing to their mostly invariant TCR α-chain usage (Vα14-Jα18 in mice, Vα24-Jα18 in humans). However, these cells have diverse TCR ß-chains, including Vß8, Vß7, and Vß2 in mice and Vß11 in humans, joined to a range of TCR Dß and Jß genes. In this study, we demonstrate that TCR ß-chain composition can dramatically influence lipid Ag recognition in an Ag-dependent manner. Namely, the glycolipids α-glucosylceramide and isoglobotrihexosylceramide were preferentially recognized by Vß7(+) NKT cells from mice, whereas the α-galactosylceramide analog OCH, with a truncated sphingosine chain, was preferentially recognized by Vß8(+) NKT cells from mice. We show that the influence of the TCR ß-chain is due to a combination of Vß-, Jß-, and CDR3ß-encoded residues and that these TCRs can recapitulate the selective Ag reactivity in TCR-transduced cell lines. Similar observations were made with human NKT cells where different CDR3ß-encoded residues determined Ag preference. These findings indicate that NKT TCR ß-chain diversity results in differential and nonhierarchical Ag recognition by these cells, which implies that some Ags can preferentially activate type I NKT cell subsets.