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