Antigen Specificity of Type I NKT Cells Is Governed by TCR β-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 alpha-chain usage (V alpha 14-J alpha 18 in mice, V alpha 24-J alpha 18 in humans). However, these cells have diverse TCR beta-chains, including V beta 8, V beta 7, and V beta 2 in mice and V beta 11 in humans, joined to a range of TCR D beta and J beta genes. In this study, we demonstrate that TCR beta-chain composition can dramatically influence lipid Ag recognition in an Ag-dependent manner. Namely, the glycolipids alpha-glucosylceramide and isoglobotrihexosylceramide were preferentially recognized by V beta 7(+) NKT cells from mice, whereas the alpha-galactosylceramide analog OCH, with a truncated sphingosine chain, was preferentially recognized by V beta 8(+) NKT cells from mice. We show that the influence of the TCR beta-chain is due to a combination of V beta-, J beta-, and CDR3 beta-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 CDR3 beta-encoded residues determined Ag preference. These findings indicate that NKT TCR beta-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.