Mechanisms imposing the Vβ bias of Vα14 natural killer T cells and consequences for microbial glycolipid recognition

Mouse and human natural killer T (NKT) cells recognize a restricted set of glycosphingolipids presented by CD1d molecules, including self iGb3 and microbial alpha-glycuronosylceramides. The importance of the canonical V alpha 14-J alpha 18 TCR alpha chain for antigen recognition by NKT cells is well recognized, but the mechanisms underlying the V beta 8, V beta 7, and V beta 2 bias in mouse have not been explored. To study the influences of thymic selection and the constraints of pairing with V alpha 14- J alpha 18, we have created a population of mature T cells expressing V alpha 14- J alpha 18 TCR alpha chain in CD1d-deficient mice and studied its recognition properties in vitro and in vivo. Transgenic cells expressed a diverse V beta repertoire but their recognition of endogenous ligands and synthetic iGb3 was restricted to the same biased V beta repertoire as expressed in natural NKT cells. In contrast alpha-GalCer, a synthetic homologue of microbial alpha-glycuronosylceramides, was recognized by a broader set of V beta chains, including the biased NKT set but also V beta 6, V beta 9, V beta 10, and V beta 14. These surprising findings demonstrate that, whereas V beta 8, V beta 7, and V beta 2 represent the optimal solution for recognition of endogenous ligand, many V beta chains that are potentially useful for the recognition of foreign lipids fail to be selected in the NKT cell repertoire.