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

Clin Exp Immunol. 2009 May;156(2):226-31. doi: 10.1111/j.1365-2249.2009.03907.x. Epub 2009 Mar 9.


Type 1 diabetes (T1D) is caused by T cell-mediated destruction of the pancreatic insulin-producing beta 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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Antigen Presentation
  • C-Peptide / chemistry
  • CD4-Positive T-Lymphocytes / immunology*
  • Cysteine / chemistry
  • Diabetes Mellitus, Type 1 / immunology*
  • Epitope Mapping
  • Epitopes, T-Lymphocyte / chemistry
  • Epitopes, T-Lymphocyte / immunology*
  • HLA-DR4 Antigen / immunology
  • Humans
  • Insulin / chemistry
  • Insulin / immunology*
  • Proinsulin / chemistry
  • Proinsulin / immunology
  • Receptors, Antigen, T-Cell / immunology


  • C-Peptide
  • Epitopes, T-Lymphocyte
  • HLA-DR4 Antigen
  • Insulin
  • Receptors, Antigen, T-Cell
  • Proinsulin
  • Cysteine