The Journal of Experimental Medicine
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Published online 31 October 2005 doi:10.1084/jem.20051251
Rockefeller University Press, 0022-1007 $8.00
JEM, Volume 202, Number 9, 1191-1197
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BRIEF DEFINITIVE REPORT

 The insulin A-chain epitope recognized by human T cells is posttranslationally modified

Stuart I. Mannering1, Leonard C. Harrison1, Nicholas A. Williamson2, Jessica S. Morris1, Daniel J. Thearle1, Kent P. Jensen1, Thomas W.H. Kay3, Jamie Rossjohn4, Ben A. Falk5, Gerald T. Nepom5, and Anthony W. Purcell2

1 Autoimmunity and Transplantation Division, The Walter and Eliza Hall Institute of Medical Research, Royal Melbourne Hospital, Parkville, Victoria 3050, Australia
2 The Department of Biochemistry and Molecular Biology and ImmunoID, The University of Melbourne, Victoria 3010, Australia
3 St. Vincent's Institute of Medical Research, Fitzroy, Victoria 3065, Australia
4 The Protein Crystallography Unit, Department of Biochemistry and Molecular Biology, Monash University, Clayton, Victoria 3800, Australia
5 Benaroya Research Institute, Seattle, WA 98101

CORRESPONDENCE Stuart I. Mannering: mannering{at}wehi.edu.au OR Anthony W. Purcell: apurcell{at}unimelb.edu.au

The autoimmune process that destroys the insulin-producing pancreatic ß cells in type 1 diabetes (T1D) is targeted at insulin and its precursor, proinsulin. T cells that recognize the proximal A-chain of human insulin were identified recently in the pancreatic lymph nodes of subjects who had T1D. To investigate the specificity of proinsulin-specific T cells in T1D, we isolated human CD4+ T cell clones to proinsulin from the blood of a donor who had T1D. The clones recognized a naturally processed, HLA DR4–restricted epitope within the first 13 amino acids of the A-chain (A1–13) of human insulin. T cell recognition was dependent on the formation of a vicinal disulfide bond between adjacent cysteine residues at A6 and A7, which did not alter binding of the peptide to HLA DR4. CD4+ T cell clones that recognized this epitope were isolated from an HLA DR4+ child with autoantibodies to insulin, and therefore, at risk for T1D, but not from two healthy HLA DR4+ donors. We define for the first time a novel posttranslational modification that is required for T cell recognition of the insulin A-chain in T1D.


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