A Molecular Basis for NKT Cell Recognition of CD1d-Self-Antigen

The antigen receptor for natural killer T cells (NKT TCR) binds CD1d-restricted microbial and self-lipid antigens, although the molecular basis of self-CD1d recognition is unclear. Here, we have characterized NKT TCR recognition of CD1d molecules loaded with natural self-antigens (Ags) and report the 2.3 Å resolution structure of an autoreactive NKT TCR-phosphatidylinositol-CD1d complex. NKT TCR recognition of self- and foreign antigens was underpinned by a similar mode of germline-encoded recognition of CD1d. However, NKT TCR autoreactivity is mediated by unique sequences within the non-germline-encoded CDR3β loop encoding for a hydrophobic motif that promotes self-association with CD1d. Accordingly, NKT cell autoreactivity may arise from the inherent affinity of the interaction between CD1d and the NKT TCR, resulting in the recognition of a broad range of CD1d-restricted self-antigens. This demonstrates that multiple self-antigens can be recognized in a similar manner by autoreactive NKT TCRs. ► Isolation and characterization of NKT TCRs interacting with self-lipid-CD1d tetramers ► Crystal structure of autoreactive NKT TCR-CD1d complex ► NKT cell autoreactivity is mediated by CDR3β loop in an antigen-independent manner ► Multiple self-antigens are recognized in a similar fashion by autoreactive NKT TCRs