This information is current as-Chain Diversity β Governed by TCR Antigen Specificity of Type I NKT Cells Is

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 a-chain usage (Va14-Ja18 in mice, Va24-Ja18 in humans). However, these cells have diverse TCR b-chains, including Vb8, Vb7, and Vb2 in mice and Vb11 in humans, joined to a range of TCR Db and Jb genes. In this study, we demonstrate that TCR b-chain composition can dramatically influence lipid Ag recognition in an Ag-dependent manner. Namely, the glycolipids a-glucosylceramide and isoglobotrihexosylceramide were preferentially recognized by Vb7 + NKT cells from mice, whereas the a-galactosylceramide analog OCH, with a truncated sphingosine chain, was preferentially recognized by Vb8 + NKT cells from mice. We show that the influence of the TCR b-chain is due to a combination of Vb-, Jb-, and CDR3b-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 CDR3b-encoded residues determined Ag preference. These findings indicate that NKT TCR b-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. N atural killer T cells are CD1d-restricted, lipid Ag–reac-tive, ab T cells that are present in mice and humans. There are two broad classes of NKT cells: the most extensively studied are those classified as type I NKT cells, which mostly express an invariant TCR a-chain paired with a limited, but not invariant, array of TCR b-chains. In contrast, type II NKT cells, although also CD1d-restricted and lipid Ag reactive, express more diverse TCR a-and b-chains and appear to recognize different lipid Ags from those detected by type I NKT cells. This study is focused on type I NKT cells, which we simply refer to as NKT cells. In mice, NKT cells typically express an invariant Va14-Ja18 TCR a-chain paired with either Vb8, Vb7, or Vb2, whereas in humans, most of these cells use the orthologous Va24-Ja18 TCR a-chain paired with Vb11 (1). However, in both mice and humans, TCR b-chain diversity is generated through the use of variable TCR Db and Jb genes and non–germline-encoded nucleotide additions during TCR b-chain gene rearrangement, thus resulting in a high level of CDR3b loop diversity and a polyclonal repertoire in both species (2–5). Furthermore, despite their limited TCR diversity, NKT cells recognize a diverse array of exogenous …