title: Individual effects of the DR11-variable beta-chain residues 67, 71, and 86 upon DR(alpha,beta 1*1101)-restricted, peptide-specific T cell proliferation.
abstract: The four members of the HLA-DR11 family of class II molecules vary only by three or fewer amino acids via dimorphisms among DR beta-chain residues 67, 71, and 86. However, they differ markedly in their abilities to induce proliferation of DR(alpha,beta 1*1101)-restricted, peptide-specific T cell clones. To dissect which DR11-variable residues, individually and in combination, mediate these functional differences, we used as APC transfectants expressing DR molecules with one of all possible permutations of DR11-variable sequences, including the four DR11 family members, and four additional DR11 variant mutants. The abilities of the wild-type or mutant molecules to present two distinct influenza peptide Ags, HA307-19 and HA128-45, to T cells was assessed in in vitro T cell proliferation assays. Of the naturally dimorphic DR11 positions, residue beta 71 variation significantly influenced the ability of DR11 molecules to present both peptides to DR(alpha,beta 1*1101)-restricted T cells. Residue beta 86 variation had relatively less influence than reported in several other DR and peptide systems. Residue beta 67 variation usually appeared irrelevant to T cell proliferation, but in two mutants led to unexpected T cell proliferation independent of nominal peptide Ag. Peptide binding, assessed by flow cytometry, was not found to be altered by any mutations that disrupted DR(alpha,beta 1*1101)-like presentation. These data indicate that residue beta 71 exerts a central role in influencing the functional differences among DR11 molecules, whereas the widely studied dimorphism of residue beta 86 is not as generally influential in DR11 as in other alleles.
authors.affiliation: Department of Immunology, G. D. Searle & Co., St. Louis, MO 63198.
authors.forename: J S
authors.initials: JS
authors.lastname: McKinney
authors.forename: X T
authors.initials: XT
authors.lastname: Fu
authors.forename: C
authors.initials: C
authors.lastname: Swearingen
authors.forename: E
authors.initials: E
authors.lastname: Klohe
authors.forename: R W
authors.initials: RW
authors.lastname: Karr
mesh_terms: D000483:Alleles; D000595:Amino Acid Sequence; D006684:HLA-DR Antigens / Q000737:chemistry* / Q000235:genetics* / Q000276:immunology; D059810:HLA-DR Serological Subtypes; D006801:Humans; D008213:Lymphocyte Activation / Q000276:immunology*; D008969:Molecular Sequence Data; D016297:Mutagenesis, Site-Directed; D010455:Peptides / Q000276:immunology; D011485:Protein Binding / Q000276:immunology; D013329:Structure-Activity Relationship; D013601:T-Lymphocytes / Q000276:immunology*
chemical_list: D006684:HLA-DR Antigens; D059810:HLA-DR Serological Subtypes; C080766:HLA-DR11 antigen; D010455:Peptides