Microbiology & Immunology - Research Publications

Permanent URI for this collection

http://hdl.handle.net/11343/226

Filters

2006 - 2008 2
2
Reset filters

Settings
Statistics
Citations
Author: Godfrey, Dale × Author: Kjer-Nielsen, Lars × Start date: 2000 × End date: 2009 ×

Search Results

Now showing 1 - 2 of 2
  • Item
    Thumbnail Image
    A minimal binding footprint on CD1d-glycolipid is a basis for selection of the unique human NKT TCR
    Wun, KS ; Borg, NA ; Kjer-Nielsen, L ; Beddoe, T ; Koh, R ; Richardson, SK ; Thakur, M ; Howell, AR ; Scott-Browne, JP ; Gapin, L ; Godfrey, DI ; McCluskey, J ; Rossjohn, J (ROCKEFELLER UNIV PRESS, 2008-04-14)
    Although it has been established how CD1 binds a variety of lipid antigens (Ag), data are only now emerging that show how alphabeta T cell receptors (TCRs) interact with CD1-Ag. Using the structure of the human semiinvariant NKT TCR-CD1d-alpha-galactosylceramide (alpha-GalCer) complex as a guide, we undertook an alanine scanning mutagenesis approach to define the energetic basis of this interaction between the NKT TCR and CD1d. Moreover, we explored how analogues of alpha-GalCer affected this interaction. The data revealed that an identical energetic footprint underpinned the human and mouse NKT TCR-CD1d-alpha-GalCer cross-reactivity. Some, but not all, of the contact residues within the Jalpha18-encoded invariant CDR3alpha loop and Vbeta11-encoded CDR2beta loop were critical for recognizing CD1d. The residues within the Valpha24-encoded CDR1alpha and CDR3alpha loops that contacted the glycolipid Ag played a smaller energetic role compared with the NKT TCR residues that contacted CD1d. Collectively, our data reveal that the region distant to the protruding Ag and directly above the F' pocket of CD1d was the principal factor in the interaction with the NKT TCR. Accordingly, although the structural footprint at the NKT TCR-CD1d-alpha-GalCer is small, the energetic footprint is smaller still, and reveals the minimal requirements for CD1d restriction.
  • Item
    Thumbnail Image
    A structural basis for selection and cross-species reactivity of the semi-invariant NKT cell receptor in CD1d/glycolipid recognition
    Kjer-Nielsen, L ; Borg, NA ; Pellicci, DG ; Beddoe, T ; Kostenko, L ; Clements, CS ; Williamson, NA ; Smyth, MJ ; Besra, GS ; Reid, HH ; Bharadwaj, M ; Godfrey, DI ; Rossjohn, J ; McCluskey, J (ROCKEFELLER UNIV PRESS, 2006-03-20)
    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.