Human and Mouse Type I Natural Killer T Cell Antigen Receptors Exhibit Different Fine Specificities for CD1d-Antigen Complex

• Published in: The Journal of biological chemistry 2012-11, Vol.287 (46), p.39139-39148
• Main Authors: Wun, Kwok S., Ross, Fiona, Patel, Onisha, Besra, Gurdyal S., Porcelli, Steven A., Richardson, Stewart K., Keshipeddy, Santosh, Howell, Amy R., Godfrey, Dale I., Rossjohn, Jamie
• Format: Article
• Language: English
• Subjects: Amino Acid Motifs; Animals; Antigen Presentation; Antigens - chemistry; Antigens, CD1d - metabolism; Crystallography, X-Ray - methods; Flow Cytometry - methods; Glycolipids - chemistry; Humans; Immunology; Leukocytes, Mononuclear - cytology; Lipids - chemistry; Mice; Models, Molecular; Molecular Conformation; Natural Killer T-Cells - immunology; Natural Killer T-Cells - metabolism; Receptor Structure-Function; Receptors, Antigen - metabolism; Structure-Activity Relationship; Surface Plasmon Resonance; T Cell Biology; X-ray Crystallography
• ISSN: 0021-9258; 1083-351X
• DOI: 10.1074/jbc.M112.412320

Human and mouse type I natural killer T (NKT) cells respond to a variety of CD1d-restricted glycolipid antigens (Ags), with their NKT cell antigen receptors (NKT TCRs) exhibiting reciprocal cross-species reactivity that is underpinned by a conserved NKT TCR-CD1d-Ag docking mode. Within this common docking footprint, the NKT TCR recognizes, to varying degrees of affinity, a range of Ags. Presently, it is unclear whether the human NKT TCRs will mirror the generalities underpinning the fine specificity of the mouse NKT TCR-CD1d-Ag interaction. Here, we assessed human NKT TCR recognition against altered glycolipid ligands of α-galactosylceramide (α-GalCer) and have determined the structures of a human NKT TCR in complex with CD1d-4′,4″-deoxy-α-GalCer and CD1d-α-GalCer with a shorter, di-unsaturated acyl chain (C20:2). Altered glycolipid ligands with acyl chain modifications did not affect the affinity of the human NKT TCR-CD1d-Ag interaction. Surprisingly, human NKT TCR recognition is more tolerant to modifications at the 4′-OH position in comparison with the 3′-OH position of α-GalCer, which contrasts the fine specificity of the mouse NKT TCR-CD1d-Ag recognition (4′-OH > 3′-OH). The fine specificity differences between human and mouse NKT TCRs was attributable to differing interactions between the respective complementarity-determining region 1α loops and the Ag. Accordingly, germline encoded fine-specificity differences underpin human and mouse type I NKT TCR interactions, which is an important consideration for therapeutic development and NKT cell physiology. Background: Natural killer T cell antigen receptors (NKT TCRs) are restricted to lipid antigens presented by CD1d. Results: Fine specificity differences between human and mouse NKT TCRs toward CD1d-antigen complexes were observed. Conclusion: A structural basis underpins the fine specificity differences between human and mouse NKT TCRs. Significance: Understanding human NKT cell response to CD1d-restricted antigens has important therapeutic implications in developing NKT cell agonists.