A public human population of TRAV26+ type II natural killer T cells recognises CD1d in a lipid-independent manner

Abstract

Most studies of CD1d-restricted natural killer T cells (NKT) have focused on type I TRAV10-TRAJ18 + NKT cells that recognise the glycolipid α-GalCer. Our understanding of type II NKT cells, their T cell receptor (TCR) gene usage, and their ligand specificity and diversity remains unclear. Here, using CD1d tetramers carrying diverse endogenous lipids (CD1d-endo), we identified public human TRAV26 + type II NKT TCRs present in all examined individuals, with many expressing a conserved TRAV26-2-TRAJ48 TCRα chain. Cellular, molecular and lipidomic analyses showed that TRAV26 + TCRs bound with similar affinities to CD1d loaded with diverse lipids, suggesting lipid-independent binding. Crystal structures of TRAV26 + TCR-CD1d complexes suggested these TCRs bound solely to the A’-roof of CD1d, distal to the protruding lipid. Collectively, we have uncovered a population of public lipid-independent TRAV26 + type II NKT cells.