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Scanning a DRB3*0101 (DR52a)-restricted epitope cross-presented by DR3: overlapping natural and artificial determinants in the human acetylcholine receptor

Nagvekar, N; Corlett, L; Jacobson, LW; Matsuo, H; Chalkley, R; Driscoll, PC; ... Willcox, N; + view all (1999) Scanning a DRB3*0101 (DR52a)-restricted epitope cross-presented by DR3: overlapping natural and artificial determinants in the human acetylcholine receptor. The Journal of Immunology , 162 (7) 4079 - 4087.

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Abstract

A recurring epitope in the human acetylcholine receptor (AChR) alpha subunit (alpha146-160) is presented to specific T cells from myasthenia gravis patients by HLA-DRB3*0101-"DR52a"-or by DR4. Here we first map residues critical for DR52a in this epitope by serial Ala substitution. For two somewhat similar T cells, this confirms the recently deduced importance of hydrophobic "anchor" residues at peptide p1 and p9; also of Asp at p4, which complements this allele's distinctive Arg74 in DRbeta. Surprisingly, despite the 9 sequence differences in DRbeta between DR52a and DR3, merely reducing the bulk of the peptide's p1 anchor residue (Trp149-->Phe) allowed maximal cross-presentation to both T cells by DR3 (which has Val86 instead of Gly). The shared K71G73R74N77 motif in the alpha helices of DR52a and DR3 thus outweighs the five differences in the floor of the peptide-binding groove. A second issue is that T cells selected in vitro with synthetic AChR peptides rarely respond to longer Ag preparations, whereas those raised with recombinant subunits consistently recognize epitopes processed naturally even from whole AChR. Here we compared one T cell of each kind, which both respond to many overlapping alpha140-160 region peptides (in proliferation assays). Even though both use Vbeta2 to recognize peptides bound to the same HLA-DR52a in the same register, the peptide-selected line nevertheless proved to depend on a recurring synthetic artifact-a widely underestimated problem. Unlike these contaminant-responsive T cells, those that are truly specific for natural AChR epitopes appear less heterogeneous and therefore more suitable targets for selective immunotherapy

Type:Article
Title:Scanning a DRB3*0101 (DR52a)-restricted epitope cross-presented by DR3: overlapping natural and artificial determinants in the human acetylcholine receptor
Additional information:UI - 99218429 LA - Eng RN - 0 (Epitopes, B-Lymphocyte) RN - 0 (Epitopes, T-Lymphocyte) RN - 0 (HLA-DR Antigens) RN - 0 (Peptides) RN - 0 (Receptors, Cholinergic) PT - JOURNAL ARTICLE DA - 19990513 IS - 0022-1767 SB - A SB - M SB - X CY - UNITED STATES JC - IFB AA - Author EM - 199907
Keywords:Epitopes, Receptor, T-Lymphocytes, HLA-DR Antigens, Antigens, peptides, United States, Alleles, Amino Acid Sequence, Amino Acid Substitution, Animal, Antigen Presentation, cell, Cell Line, CELLS, chemical synthesis, chemistry, Epitopes, B-Lymphocyte, Epitopes, T-Lymphocyte, genetics, immunology, In Vitro, metabolism, Mice, Molecular Sequence Data, Myasthenia Gravis, Protein Binding, Receptors, Cholinergic, Support, Non-U.S.Gov't, Torpedo, recombinant
UCL classification:UCL > School of Life and Medical Sciences > Faculty of Life Sciences > Biosciences (Division of)

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