title: Recognition of β-linked self glycolipids mediated by natural killer T cell antigen receptors.
abstract: The most potent foreign antigens for natural killer T cells (NKT cells) are α-linked glycolipids, whereas NKT cell self-reactivity involves weaker recognition of structurally distinct β-linked glycolipid antigens. Here we provide the mechanism for the autoreactivity of T cell antigen receptors (TCRs) on NKT cells to the mono- and tri-glycosylated β-linked agonists β-galactosylceramide (β-GalCer) and isoglobotrihexosylceramide (iGb3), respectively. In binding these disparate antigens, the NKT cell TCRs docked onto CD1d similarly, achieving this by flattening the conformation of the β-linked ligands regardless of the size of the glycosyl head group. Unexpectedly, the antigenicity of iGb3 was attributable to its terminal sugar group making compensatory interactions with CD1d. Thus, the NKT cell TCR molds the β-linked self ligands to resemble the conformation of foreign α-linked ligands, which shows that induced-fit molecular mimicry can underpin the self-reactivity of NKT cell TCRs to β-linked antigens.
authors.affiliation: Department of Microbiology & Immunology, University of Melbourne, Parkville, Victoria, Australia.
authors.forename: Daniel G
authors.initials: DG
authors.lastname: Pellicci
authors.forename: Andrew J
authors.initials: AJ
authors.lastname: Clarke
authors.forename: Onisha
authors.initials: O
authors.lastname: Patel
authors.forename: Thierry
authors.initials: T
authors.lastname: Mallevaey
authors.forename: Travis
authors.initials: T
authors.lastname: Beddoe
authors.forename: Jérôme
authors.initials: J
authors.lastname: Le Nours
authors.forename: Adam P
authors.initials: AP
authors.lastname: Uldrich
authors.forename: James
authors.initials: J
authors.lastname: McCluskey
authors.forename: Gurdyal S
authors.initials: GS
authors.lastname: Besra
authors.forename: Steven A
authors.initials: SA
authors.lastname: Porcelli
authors.forename: Laurent
authors.initials: L
authors.lastname: Gapin
authors.forename: Dale I
authors.initials: DI
authors.lastname: Godfrey
authors.forename: Jamie
authors.initials: J
authors.lastname: Rossjohn
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D055610:Antigens, CD1d / Q000737:chemistry / Q000276:immunology* / Q000378:metabolism; D015551:Autoimmunity; D001665:Binding Sites; D018360:Crystallography, X-Ray; D005434:Flow Cytometry; D005699:Galactosylceramides / Q000737:chemistry / Q000276:immunology* / Q000378:metabolism; D005915:Globosides / Q000737:chemistry / Q000276:immunology* / Q000378:metabolism; D006801:Humans; D006825:Hybridomas; D007700:Kinetics; D051379:Mice; D008958:Models, Molecular; D018716:Molecular Mimicry; D008969:Molecular Sequence Data; D055611:Natural Killer T-Cells / Q000166:cytology / Q000276:immunology* / Q000378:metabolism; D011485:Protein Binding / Q000276:immunology; D015202:Protein Engineering / Q000379:methods; D016693:Receptors, Antigen, T-Cell, alpha-beta / Q000737:chemistry / Q000276:immunology / Q000378:metabolism; D013329:Structure-Activity Relationship; D020349:Surface Plasmon Resonance; D014281:Trihexosylceramides / Q000737:chemistry / Q000276:immunology* / Q000378:metabolism
chemical_list: D055610:Antigens, CD1d; D005699:Galactosylceramides; D005915:Globosides; D016693:Receptors, Antigen, T-Cell, alpha-beta; D014281:Trihexosylceramides; C514781:isoglobotrihexosylceramide