Little is known regarding the basis for selection of the semi-invariant αβ 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 CDR3β composition and length. Both TCRs contain a conserved, positively charged pocket at the ligand interface that is lined by residues from the invariant TCR α- and semi-invariant β-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 CDR3β 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 CDR3α 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 αβ TCR and the unique antigen specificity of NKT cells.
A structural basis for selection and cross-species reactivity of the semi-invariant NKT cell receptor in CD1d/glycolipid recognition
Abbreviations used: α-GalCer, α-galactosylceramide; Ag, antigen; BSA, buried surface area; C, constant; CDR, complementarity-determining region; hCD1d, human CD1d; mCD1d, mouse CD1d; RMS, root mean square; SPR, surface plasmon resonance; V, variable.
L. Kjer-Nielsen and N.A. Borg contributed equally to this work.
J. McCluskey and J. Rossjohn contributed equally to this work.
Lars Kjer-Nielsen, Natalie A. Borg, Daniel G. Pellicci, Travis Beddoe, Lyudmila Kostenko, Craig S. Clements, Nicholas A. Williamson, Mark J. Smyth, Gurdyal S. Besra, Hugh H. Reid, Mandvi Bharadwaj, Dale I. Godfrey, Jamie Rossjohn, James McCluskey; A structural basis for selection and cross-species reactivity of the semi-invariant NKT cell receptor in CD1d/glycolipid recognition . J Exp Med 20 March 2006; 203 (3): 661–673. doi: https://doi.org/10.1084/jem.20051777
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