Natural killer T cell antigen receptors (NKT TCRs) recognize lipid-based antigens (Ags) presented by CD1d. Although the TCR alpha-chain is invariant, NKT TCR V beta exhibits greater diversity, with one (V beta 11) and three (V beta 8, V beta 7, and V beta 2) V beta chains in humans and mice, respectively. With the exception of the V beta 2 NKT TCR, NKT TCRs possess canonical tyrosine residues within complementarity determining region (CDR) 2 beta that are critical for CD1d binding. Thus, how V beta 2 NKT TCR docks with CD1d-Ag was unclear. Despite the absence of the CDR2 beta-encoded tyrosine residues, we show that the V beta 2 NKT TCR engaged CD1d-Ag in a similar manner and with a comparable affinity and energetic footprint to the manner observed for the V beta 8.2 and V beta 7 NKT TCRs. Accordingly, the germline-encoded regions of the TCR beta-chain do not exclusively dictate the innate NKT TCR-CD1d-Ag docking mode. Nevertheless, clear fine specificity differences for the CD1d-Ag existed between the V beta 2 NKT TCR and the V beta 8.2 and V beta 7 NKT TCRs, with the V beta 2 NKT TCR exhibiting greater sensitivity to modifications to the glycolipid Ag. Furthermore, within the V beta 2 NKT TCR-CD1d-alpha GalCer complex, the CDR2 beta loop mediated fewer contacts with CD1d, whereas the CDR1 beta and CDR3 beta loops contacted CD1d to a much greater extent compared with most V beta 11, V beta 8.2, and V beta 7 NKT TCRs. Accordingly, there is a greater interplay between the germline-and nongermline-encoded loops within the TCR beta-chain of the V beta 2 NKT TCR that enables CD1d-Ag ligation.
- T cell repertoire
- conserved docking