A conserved human population of TRAV26+ type II Natural Killer T cells solely recognise CD1d

Most studies of CD1d-restricted Natural killer T cells (NKT) have focussed on type I TRAV10-TRAJ18 ⁺ NKT cells that recognise the glycolipid a-GalCer. Our understanding of type II NKT cells, their TCR gene usage and ligand 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 individuals, with many expressing a conserved TRAV26-2-TRAJ48 TCRa 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 showed these TCRs bound solely to the A'-roof of CD1d, distant from the protruding lipid. Collectively we have uncovered a population of public lipid-independent TRAV26 ⁺ type II NKT cells, suggesting a potential role in diseases where aberrant CD1d expression occurs.