Recognition of a Subregion of Human Proinsulin by Class I-Restricted T Cells in Type 1 Diabetic Patients

• Published in: Proceedings of the National Academy of Sciences - PNAS Vol. 102; no. 30; pp. 10581 - 10586
• Main Authors: Toma, Andréa, Haddouk, Samy, Briand, Jean-Paul, Camoin, Luc, Gahery, Hanne, Connan, Francine, Dubois-Laforgue, Danielle, Caillat-Zucman, Sophie, Guillet, Jean-Gérard, Carel, Jean-Claude, Muller, Sylviane, Choppin, Jeannine, Boitard, Christian, McDevitt, Hugh O.
• Format: Journal Article
• Language: English
• Published: United States National Academy of Sciences 26.07.2005; National Acad Sciences
• Subjects: Adult; Aged; Beta cells; Biological Sciences; CD8-Positive T-Lymphocytes - immunology; Diabetes; Diabetes complications; Diabetes Mellitus, Type 1 - immunology; Epitopes; Female; Histocompatibility Antigens Class I - metabolism; HLA antigens; Humans; Immunoenzyme Techniques; Insulin; Interferon-gamma - immunology; Male; Mass Spectrometry; Middle Aged; Molecules; Proinsulin - immunology; Proinsulin - metabolism; T lymphocytes; Type 1 diabetes mellitus; Type 2 diabetes mellitus
• ISSN: 0027-8424; 1091-6490
• DOI: 10.1073/pnas.0504230102

Proinsulin is a key autoantigen in type 1 diabetes. Evidence in the mouse has underscored the importance of the insulin B chain region in autoimmunity to pancreatic beta cells. In man, a majority of proteasome cleavage sites are predicted by proteasome cleavage algorithms within this region. To study CD8+T cell responses to the insulin B chain and adjacent C peptide, we selected 8- to 11-mer peptides according to proteasome cleavage patterns obtained by digestion of two peptides covering proinsulin residues 28 to 64. We studied their binding to purified HLA class I molecules and their recognition by T cells from diabetic patients. Peripheral blood mononuclear cells from 17 of 19 recent-onset and 12 of 13 long-standing type 1 diabetic patients produced IFN-γ in response to proinsulin peptides as shown by using an ELISPOT assay. In most patients, the response was against several class I-restricted peptides. Nine peptides were recognized within the proinsulin region covering residues 34 to 61. Four yielded a high frequency of recognition in HLA-A1 and -B8 patients. Three peptides located in the proinsulin region 41-51 were shown to bind several HLA molecules and to be recognized in a high percentage of diabetic patients.