title: Molecular analysis of a heteroclitic T cell response to the immunodominant epitope of sperm whale myoglobin. Implications for peptide partial agonists.
abstract: We have investigated the molecular basis for binding and Ag presentation of an immunodominant Th cell determinant of sperm whale myoglobin, a prototype amphipathic helical structure in the native protein. A series of peptides with three different substitutions at each position were evaluated for binding to the class II MHC molecule I-Ad and for activation of two T cell clones with distinct fine specificity, to determine the role of each residue. The assignment of MHC binding and TCR binding residues is consistent with a peptide bound as a twisted beta-strand, with 130 degrees twist similar to that of the influenza hemagglutinin peptide crystallized in the groove of HLA-DR1. This twist gives the peptide amphipathicity, with a periodicity similar to an alpha-helix without its being a helix. Two substituted peptides were discovered to be heteroclitic, but by different molecular mechanisms, one involving gain of a favorable residue and one involving loss of an unfavorable one. Complexes of both peptides with I-Ad had enormously higher affinity for the TCR, but peptide affinity for the MHC molecule was not increased, such that the wild-type peptide acted as a partial agonist and inhibited the response to the heteroclitic ones. Moreover, the magnitude of response was elevated in a way that could not be mimicked by the wild-type peptide even at higher concentration. These results suggest a TCR dwell time requirement for optimal signal transduction that may help explain the mechanism of partial agonism.
authors.affiliation: Molecular Immunogenetics and Vaccine Research Section, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892, USA.
authors.forename: R D
authors.initials: RD
authors.lastname: England
authors.forename: M C
authors.initials: MC
authors.lastname: Kullberg
authors.forename: J L
authors.initials: JL
authors.lastname: Cornette
authors.forename: J A
authors.initials: JA
authors.lastname: Berzofsky
mesh_terms: D000595:Amino Acid Sequence; D000596:Amino Acids / Q000502:physiology; D000818:Animals; D001667:Binding, Competitive; D005260:Female; D016056:Immunodominant Epitopes / Q000276:immunology*; D008213:Lymphocyte Activation / Q000187:drug effects; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D008969:Molecular Sequence Data; D009211:Myoglobin / Q000276:immunology*; D010446:Peptide Fragments / Q000138:chemical synthesis / Q000276:immunology* / Q000502:physiology; D013601:T-Lymphocytes / Q000276:immunology*; D014907:Whales / Q000276:immunology*
chemical_list: D000596:Amino Acids; D016056:Immunodominant Epitopes; D009211:Myoglobin; D010446:Peptide Fragments