A structural basis for selection and cross-species reactivity of the semi-invariant NKT cell receptor in CD1d/glycolipid recognition.
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.
Kjer-Nielsen
Lars
L
Department of Microbiology and Immunology, University of Melbourne, Parkville, Victoria 3010, Australia.
Borg
Natalie A
NA
Pellicci
Daniel G
DG
Beddoe
Travis
T
Kostenko
Lyudmila
L
Clements
Craig S
CS
Williamson
Nicholas A
NA
Smyth
Mark J
MJ
Besra
Gurdyal S
GS
Reid
Hugh H
HH
Bharadwaj
Mandvi
M
Godfrey
Dale I
DI
Rossjohn
Jamie
J
McCluskey
James
J
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*
D018949:Antigens, CD1; D006017:Glycolipids; D016693:Receptors, Antigen, T-Cell, alpha-beta