A-chain of insulin is a hot-spot for CD4⁺ T cell epitopes in human type 1 diabetes

• Published in: Clinical and experimental immunology Vol. 156; no. 2; pp. 226 - 231
• Main Authors: Mannering, S.I, Pang, S.H, Williamson, N.A, Naselli, G, Reynolds, E.C, O'Brien-Simpson, N.M, Purcell, A.W, Harrison, L.C
• Format: Journal Article
• Language: English
• Published: Oxford, UK Oxford, UK : Blackwell Publishing Ltd 01.05.2009; Blackwell Publishing Ltd; Blackwell; Blackwell Science Inc
• Subjects: Analytical, structural and metabolic biochemistry; Antigen Presentation; Biological and medical sciences; C-Peptide - chemistry; CD4; CD4-Positive T-Lymphocytes - immunology; Cysteine - chemistry; Diabetes Mellitus, Type 1 - immunology; Diabetes. Impaired glucose tolerance; Endocrine pancreas. Apud cells (diseases); Endocrinopathies; epitope; Epitope Mapping; Epitopes, T-Lymphocyte - chemistry; Epitopes, T-Lymphocyte - immunology; Etiopathogenesis. Screening. Investigations. Target tissue resistance; Fundamental and applied biological sciences. Psychology; HLA-DR4 Antigen - immunology; Humans; Insulin - chemistry; Insulin - immunology; insulin-dependent diabetes mellitus; Medical sciences; proinsulin; Proinsulin - chemistry; Proinsulin - immunology; Receptors, Antigen, T-Cell - immunology; T cell; Translational Studies; type 1 diabetes; Endocrinopathy; Human; Proinsulin; Immunopathology; Pancreatic hormone; CD4 T lymphocyte; Antigenic determinant; Hot spot; T cell; Autoimmune disease; Biochemistry; Prohormone; Insulin; CD4; Type 1 diabetes; T-Lymphocyte; epitope
• ISSN: 0009-9104; 1365-2249
• DOI: 10.1111/j.1365-2249.2009.03907.x

Type 1 diabetes (T1D) is caused by T cell-mediated destruction of the pancreatic insulin-producing β cells. While the role of CD4⁺ T cells in the pathogenesis of T1D is accepted widely, the epitopes recognized by pathogenic human CD4⁺ T cells remain poorly defined. None the less, responses to the N-terminal region of the insulin A-chain have been described. Human CD4⁺ T cells from the pancreatic lymph nodes of subjects with T1D respond to the first 15 amino acids of the insulin A-chain. We identified a human leucocyte antigen-DR4-restricted epitope comprising the first 13 amino acids of the insulin A-chain (A1-13), dependent upon generation of a vicinal disulphide bond between adjacent cysteines (A6-A7). Here we describe the analysis of a CD4⁺ T cell clone, isolated from a subject with T1D, which recognizes a new HLR-DR4-restricted epitope (KRGIVEQCCTSICS) that overlaps the insulin A1-13 epitope. This is a novel epitope, because the clone responds to proinsulin but not to insulin, T cell recognition requires the last two residues of the C-peptide (Lys, Arg) and recognition does not depend upon a vicinal disulphide bond between the A6 and A7 cysteines. The finding of a further CD4⁺ T cell epitope in the N-terminal A-chain region of human insulin underscores the importance of this region as a target of CD4⁺ T cell responses in human T1D.