Epitopes described in "Recognition of human proinsulin leader sequence by class I-restricted T-cells in HLA-A*0201 transgenic mice and in human type 1 diabetes."

Article Authors:Andréa Toma; Taghrid Laïka; Samy Haddouk; Sandrine Luce; Jean-Paul Briand; Luc Camoin; Francine Connan; Marion Lambert; Sophie Caillat-Zucman; Jean-Claude Carel; Sylviane Muller; Jeannine Choppin; François Lemonnier; Christian Boitard
Article Title:Recognition of human proinsulin leader sequence by class I-restricted T-cells in HLA-A*0201 transgenic mice and in human type 1 diabetes.
Reference Detail
Reference ID:1013773
Abstract:OBJECTIVE: A restricted region of proinsulin located in the B chain and adjacent region of C-peptide has been shown to contain numerous candidate epitopes recognized by CD8(+) T-cells. Our objective is to characterize HLA class I-restricted epitopes located within the preproinsulin leader sequence. RESEARCH DESIGN AND METHODS: Seven 8- to 11-mer preproinsulin peptides carrying anchoring residues for HLA-A1, -A2, -A24, and -B8 were selected from databases. HLA-A2-restricted peptides were tested for immunogenicity in transgenic mice expressing a chimeric HLA-A*0201/beta2-microglobulin molecule. The peptides were studied for binding to purified HLA class I molecules, selected for carrying COOH-terminal residues generated by proteasome digestion in vitro and tested for recognition by human lymphocytes using an ex vivo interferon-gamma (IFN-gamma) ELISpot assay. RESULTS: Five HLA-A2-restricted peptides were immunogenic in transgenic mice. Murine T-cell clones specific for these peptides were cytotoxic against cells transfected with the preproinsulin gene. They were recognized by peripheral blood mononuclear cells (PBMCs) from 17 of 21 HLA-A2 type 1 diabetic patients. PBMCs from 25 of 38 HLA-A1, -A2, -A24, or -B8 patients produced IFN-gamma in response to six preproinsulin peptides covering residues 2-25 within the preproinsulin region. In most patients, the response was against several class I-restricted peptides. T-cells recognizing preproinsulin peptide were characterized as CD8(+) T-cells by staining with peptide/HLA-A2 tetramers. CONCLUSIONS: We defined class I-restricted epitopes located within the leader sequence of human preproinsulin through in vivo (transgenic mice) and ex vivo (diabetic patients) assays, illustrating the possible role of preproinsulin-specific CD8(+) T-cells in human type 1 diabetes.
Affiliations:Institut National de Santé et de Recherche Médicale U561 et Université Paris N, Hôpital Cochin-Saint Vincent de Paul, Paris, France.
Reference Type:Literature
PubMed ID:19011169
Journal Volume:58
Article Pages:394-402
Journal ISSN:1939-327X
Article Chemical List:Epitopes;HLA Antigens;Peptide Fragments;Proinsulin;Proteasome Endopeptidase Complex
Article MeSH List:Animals; CD8-Positive T-Lymphocytes(immunology); Cell Line; Diabetes Mellitus, Type 1(genetics; immunology; metabolism); Enzyme-Linked Immunosorbent Assay; Epitopes(immunology); Female; HLA Antigens(genetics; immunology); Humans; Male; Mice; Mice, Transgenic; Peptide Fragments(immunology); Proinsulin(immunology); Proteasome Endopeptidase Complex(metabolism)
Curation Last Updated:2015-06-05 01:29:34