title: Metal-specific CD4+ T-cell responses induced by beryllium exposure in HLA-DP2 transgenic mice.
abstract: Chronic beryllium disease (CBD) is a granulomatous lung disorder that is associated with the accumulation of beryllium (Be)-specific CD4(+) T cells into the lung. Genetic susceptibility is linked to HLA-DPB1 alleles that possess a glutamic acid at position 69 (βGlu69), and HLA-DPB1*02:01 is the most prevalent βGlu69-containing allele. Using HLA-DP2 transgenic (Tg) mice, we developed a model of CBD that replicates the major features of the human disease. Here we characterized the T-cell receptor (TCR) repertoire of Be-responsive CD4(+) T cells derived from the lungs of Be oxide-exposed HLA-DP2 Tg mice. The majority of Be-specific T-cell hybridomas expressed TCR Vβ6, and a subset of these hybridomas expressed identical or nearly identical β-chains that were paired with different α-chains. We delineated mimotopes that bind to HLA-DP2 and form a complex recognized by Be-specific CD4(+) T cells in the absence of Be. These Be-independent peptides possess an arginine at p5 and a tryptophan at p7 that surround the Be-binding site within the HLA-DP2 acidic pocket and likely induce charge and conformational changes that mimic those induced by the Be(2+) cation. Collectively, these data highlight the interplay between peptides and Be in the generation of an adaptive immune response in metal-induced hypersensitivity.
authors.affiliation: Department of Medicine, University of Colorado Anschutz Medical Campus, Aurora, Colorado, USA.
authors.forename: M T
authors.initials: MT
authors.lastname: Falta
authors.affiliation: Department of Medicine, University of Colorado Anschutz Medical Campus, Aurora, Colorado, USA.
authors.forename: A N
authors.initials: AN
authors.lastname: Tinega
authors.affiliation: Department of Medicine, University of Colorado Anschutz Medical Campus, Aurora, Colorado, USA.
authors.forename: D G
authors.initials: DG
authors.lastname: Mack
authors.affiliation: Department of Medicine, University of Colorado Anschutz Medical Campus, Aurora, Colorado, USA.
authors.forename: N A
authors.initials: NA
authors.lastname: Bowerman
authors.affiliation: Department of Immunology, University of Colorado Anschutz Medical Campus, Aurora, Colorado, USA.|Howard Hughes Medical Institute, National Jewish Health, Denver, Colorado, USA.
authors.forename: F
authors.initials: F
authors.lastname: Crawford
authors.affiliation: Department of Immunology, University of Colorado Anschutz Medical Campus, Aurora, Colorado, USA.|Howard Hughes Medical Institute, National Jewish Health, Denver, Colorado, USA.
authors.forename: J W
authors.initials: JW
authors.lastname: Kappler
authors.affiliation: Torrey Pines Institute for Molecular Studies, San Diego, California, USA.
authors.forename: C
authors.initials: C
authors.lastname: Pinilla
authors.affiliation: Department of Medicine, University of Colorado Anschutz Medical Campus, Aurora, Colorado, USA.|Department of Immunology, University of Colorado Anschutz Medical Campus, Aurora, Colorado, USA.
authors.forename: A P
authors.initials: AP
authors.lastname: Fontenot
mesh_terms: D020816:Amino Acid Motifs; D000818:Animals; D001607:Berylliosis / Q000209:etiology / Q000235:genetics / Q000276:immunology* / Q000473:pathology; D001608:Beryllium / Q000633:toxicity; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology* / Q000473:pathology; D004195:Disease Models, Animal; D018604:Epitope Mapping; D018984:Epitopes, T-Lymphocyte / Q000737:chemistry / Q000235:genetics / Q000276:immunology*; D015870:Gene Expression; D020022:Genetic Predisposition to Disease; D059868:HLA-DP beta-Chains / Q000737:chemistry / Q000235:genetics / Q000276:immunology*; D006801:Humans; D006825:Hybridomas / Q000737:chemistry / Q000276:immunology; D008168:Lung / Q000187:drug effects / Q000276:immunology / Q000473:pathology; D051379:Mice; D008822:Mice, Transgenic; D008969:Molecular Sequence Data; D016693:Receptors, Antigen, T-Cell, alpha-beta / Q000737:chemistry / Q000235:genetics / Q000276:immunology*; D055672:Static Electricity
chemical_list: D018984:Epitopes, T-Lymphocyte; D059868:HLA-DP beta-Chains; C083176:HLA-DPw2 antigen; D016693:Receptors, Antigen, T-Cell, alpha-beta; C032777:beryllium oxide; D001608:Beryllium