title: The paradox of immune molecular recognition of alpha-galactosylceramide: low affinity, low specificity for CD1d, high affinity for alpha beta TCRs.
abstract: CD1 resembles both class I and class II MHC but differs by the important aspect of presenting lipid/glycolipids, instead of peptides, to T cells. Biophysical studies of lipid/CD1 interactions have been limited, and kinetics of binding are in contradiction with functional studies. We have revisited this issue by designing new assays to examine the loading of CD1 with lipids. As expected for hydrophobic interactions, binding affinity was not high and had limited specificity. Lipid critical micelle concentration set the limitation to these studies. Once loaded onto CD1d, the recognition of glycolipids by alphabeta T cell receptor was studied by surface plasmon resonance using soluble Valpha14-Vbeta8.2 T cell receptors. The Valpha14 Jalpha18 chain could be paired with NK1.1 cell-derived Vbeta chain, or any Vbeta8 chain, to achieve high affinity recognition of alpha-galactosylceramide. Biophysical analysis indicated little effect of temperature or ionic strength on the binding interaction, in contrast to what has been seen in peptide/MHC-TCR studies. This suggests that there is less accommodation made by this TCR in recognizing alpha-galactosylceramide, and it can be assumed that the most rigid part of the Ag, the sugar moiety, is critical in the interaction.
authors.affiliation: Department of Immunology, The Scripps Research Institute, La Jolla, CA 92037, USA.
authors.forename: Carlos
authors.initials: C
authors.lastname: Cantu
authors.forename: Kamel
authors.initials: K
authors.lastname: Benlagha
authors.forename: Paul B
authors.initials: PB
authors.lastname: Savage
authors.forename: Albert
authors.initials: A
authors.lastname: Bendelac
authors.forename: Luc
authors.initials: L
authors.lastname: Teyton
mesh_terms: D000818:Animals; D017951:Antigen Presentation / Q000276:immunology*; D018949:Antigens, CD1 / Q000276:immunology* / Q000378:metabolism*; D055610:Antigens, CD1d; D001665:Binding Sites / Q000276:immunology; D002151:Calorimetry / Q000379:methods; D002460:Cell Line; D019281:Dimerization; D018984:Epitopes, T-Lymphocyte / Q000276:immunology* / Q000378:metabolism*; D005699:Galactosylceramides / Q000276:immunology* / Q000378:metabolism*; D019673:Genes, T-Cell Receptor alpha; D019674:Genes, T-Cell Receptor beta; D007525:Isoelectric Focusing / Q000379:methods; D007694:Killer Cells, Natural / Q000276:immunology / Q000378:metabolism; D007700:Kinetics; D008213:Lymphocyte Activation; D051379:Mice; D011485:Protein Binding / Q000276:immunology; D016693:Receptors, Antigen, T-Cell, alpha-beta / Q000096:biosynthesis / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D011994:Recombinant Proteins / Q000096:biosynthesis / Q000737:chemistry / Q000378:metabolism; D016176:T-Lymphocyte Subsets / Q000276:immunology / Q000378:metabolism; D013816:Thermodynamics; D014162:Transfection
chemical_list: D018949:Antigens, CD1; D055610:Antigens, CD1d; D018984:Epitopes, T-Lymphocyte; D005699:Galactosylceramides; D016693:Receptors, Antigen, T-Cell, alpha-beta; D011994:Recombinant Proteins