Atypical T cell receptor usage defines a population of Natural Killer T cells with distinct glycolipid antigen recognition properties (160.13)

Abstract

Abstract Lipid Ag reactive T cells represent an important component of the T cell repertoire. The most well studied example is the classical (or Type-1) NKT cells that respond to the glycolipid Ag α-galactosylceramide (α-GalCer) presented by CD1d. While often referred to as 'invariant' due to the expression of an invariant TCR-α chain (Vα14-Jα18), in fact, Type-1 NKT cells carry a diverse TCR-β repertoire that influences Ag recognition. Furthermore, we have identified a completely novel population of NKT cells (Type-1A cells), that expresses a previously unidentified, canonical, Vα10-Jα50 TCR α-chain. These cells exhibit a different pattern of glycolipid Ag reactivity, including a preference for α-glucosylceramide (α-GlcCer) over α-GalCer and a bias towards Th2 cytokine production. Two populations of Type-1A NKT cells (TCRhi and TCRlo) are present in the thymus and they also have diverse TCR-β chains. We also provide the first structural analysis of a non-classical NKT TCR-CD1d-glycolipid complex, showing that the Type-1A TCR-CD1d-α-GlcCer complex displayed a similar docking mode to that of Type-1 NKT TCRs, although differences at the Ag-binding interfaces accounted for the altered specificity. The discovery of a second invariant TCR α-chain expressed by CD1d-restricted NKT cells provides new insights into the repertoire diversity and its influence on glycolipid recognition by NKT cells, and has significant implications for the immunologic role of glycolipid-specific T cell responses.