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

Authors

  • S. I. Mannering,

    1. Autoimmunity and Transplantation Division, The Walter and Eliza Hall Institute of Medical Research, 1G Royal Parade, Parkville,
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    • 1

      Current address: St Vincent's Institute, The University of Melbourne Department of Medicine, St Vincent's Hospital, 9 Princes Street, Fitzroy, Victoria, Australia.

  • S. H. Pang,

    1. Autoimmunity and Transplantation Division, The Walter and Eliza Hall Institute of Medical Research, 1G Royal Parade, Parkville,
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  • N. A. Williamson,

    1. The Department of Biochemistry and Molecular Biology and The Bio21 Molecular Science and Biotechnology Institute, The University of Melbourne, and
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  • G. Naselli,

    1. Autoimmunity and Transplantation Division, The Walter and Eliza Hall Institute of Medical Research, 1G Royal Parade, Parkville,
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  • E. C. Reynolds,

    1. The Melbourne Dental School, CRC for Oral Health Science, The University of Melbourne, Melbourne, Victoria, Australia
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  • N. M. O'Brien-Simpson,

    1. The Melbourne Dental School, CRC for Oral Health Science, The University of Melbourne, Melbourne, Victoria, Australia
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  • A. W. Purcell,

    1. The Department of Biochemistry and Molecular Biology and The Bio21 Molecular Science and Biotechnology Institute, The University of Melbourne, and
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  • L. C. Harrison

    1. Autoimmunity and Transplantation Division, The Walter and Eliza Hall Institute of Medical Research, 1G Royal Parade, Parkville,
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S. I. Mannering, St Vincent's Institute, 9 Princes Street, Fitzroy, Victoria 3065, Australia.
E-mail: smannering@svi.edu.au

Summary

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.

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