title: A structural basis for selection and cross-species reactivity of the semi-invariant NKT cell receptor in CD1d/glycolipid recognition.
abstract: Little is known regarding the basis for selection of the semi-invariant alphabeta T cell receptor (TCR) expressed by natural killer T (NKT) cells or how this mediates recognition of CD1d-glycolipid complexes. We have determined the structures of two human NKT TCRs that differ in their CDR3beta composition and length. Both TCRs contain a conserved, positively charged pocket at the ligand interface that is lined by residues from the invariant TCR alpha- and semi-invariant beta-chains. The cavity is centrally located and ideally suited to interact with the exposed glycosyl head group of glycolipid antigens. Sequences common to mouse and human invariant NKT TCRs reveal a contiguous conserved "hot spot" that provides a basis for the reactivity of NKT cells across species. Structural and functional data suggest that the CDR3beta loop provides a plasticity mechanism that accommodates recognition of a variety of glycolipid antigens presented by CD1d. We propose a model of NKT TCR-CD1d-glycolipid interaction in which the invariant CDR3alpha loop is predicted to play a major role in determining the inherent bias toward CD1d. The findings define a structural basis for the selection of the semi-invariant alphabeta TCR and the unique antigen specificity of NKT cells.
authors.affiliation: Department of Microbiology and Immunology, University of Melbourne, Parkville, Victoria 3010, Australia.
authors.forename: Lars
authors.initials: L
authors.lastname: Kjer-Nielsen
authors.forename: Natalie A
authors.initials: NA
authors.lastname: Borg
authors.forename: Daniel G
authors.initials: DG
authors.lastname: Pellicci
authors.forename: Travis
authors.initials: T
authors.lastname: Beddoe
authors.forename: Lyudmila
authors.initials: L
authors.lastname: Kostenko
authors.forename: Craig S
authors.initials: CS
authors.lastname: Clements
authors.forename: Nicholas A
authors.initials: NA
authors.lastname: Williamson
authors.forename: Mark J
authors.initials: MJ
authors.lastname: Smyth
authors.forename: Gurdyal S
authors.initials: GS
authors.lastname: Besra
authors.forename: Hugh H
authors.initials: HH
authors.lastname: Reid
authors.forename: Mandvi
authors.initials: M
authors.lastname: Bharadwaj
authors.forename: Dale I
authors.initials: DI
authors.lastname: Godfrey
authors.forename: Jamie
authors.initials: J
authors.lastname: Rossjohn
authors.forename: James
authors.initials: J
authors.lastname: McCluskey
mesh_terms: D000818:Animals; D017951:Antigen Presentation / Q000235:genetics / Q000276:immunology*; D018949:Antigens, CD1 / Q000235:genetics / Q000276:immunology*; D019673:Genes, T-Cell Receptor alpha / Q000235:genetics / Q000276:immunology; D019674:Genes, T-Cell Receptor beta / Q000235:genetics / Q000276:immunology; D006017:Glycolipids / Q000276:immunology*; D006801:Humans; D007694:Killer Cells, Natural / Q000276:immunology*; D051379:Mice; D011485:Protein Binding / Q000235:genetics / Q000276:immunology; D020836:Protein Structure, Quaternary; D017434:Protein Structure, Tertiary / Q000502:physiology; D016693:Receptors, Antigen, T-Cell, alpha-beta / Q000276:immunology*; D013045:Species Specificity; D040681:Structural Homology, Protein; D013329:Structure-Activity Relationship; D013601:T-Lymphocytes / Q000276:immunology*
chemical_list: D018949:Antigens, CD1; D006017:Glycolipids; D016693:Receptors, Antigen, T-Cell, alpha-beta