title: Human and mouse type I natural killer T cell antigen receptors exhibit different fine specificities for CD1d-antigen complex.
abstract: 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.
authors.affiliation: Australian Research Council (ARC) Centre of Excellence in Structural and Functional Microbial Genomics, Department of Biochemistry and Molecular Biology, School of Biomedical Sciences, Monash University, Clayton, Victoria 3800, Australia.
authors.forename: Kwok S
authors.initials: KS
authors.lastname: Wun
authors.forename: Fiona
authors.initials: F
authors.lastname: Ross
authors.forename: Onisha
authors.initials: O
authors.lastname: Patel
authors.forename: Gurdyal S
authors.initials: GS
authors.lastname: Besra
authors.forename: Steven A
authors.initials: SA
authors.lastname: Porcelli
authors.forename: Stewart K
authors.initials: SK
authors.lastname: Richardson
authors.forename: Santosh
authors.initials: S
authors.lastname: Keshipeddy
authors.forename: Amy R
authors.initials: AR
authors.lastname: Howell
authors.forename: Dale I
authors.initials: DI
authors.lastname: Godfrey
authors.forename: Jamie
authors.initials: J
authors.lastname: Rossjohn
mesh_terms: D020816:Amino Acid Motifs; D000818:Animals; D017951:Antigen Presentation; D000941:Antigens / Q000737:chemistry; D055610:Antigens, CD1d / Q000378:metabolism*; D018360:Crystallography, X-Ray / Q000379:methods; D005434:Flow Cytometry / Q000379:methods; D006017:Glycolipids / Q000737:chemistry; D006801:Humans; D007963:Leukocytes, Mononuclear / Q000166:cytology; D008055:Lipids / Q000737:chemistry; D051379:Mice; D008958:Models, Molecular; D008968:Molecular Conformation; D055611:Natural Killer T-Cells / Q000276:immunology* / Q000378:metabolism; D011946:Receptors, Antigen / Q000378:metabolism*; D013329:Structure-Activity Relationship; D020349:Surface Plasmon Resonance
chemical_list: D000941:Antigens; D055610:Antigens, CD1d; D006017:Glycolipids; D008055:Lipids; D011946:Receptors, Antigen