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


Mannering, SI; Harrison, LC; Williamson, NA; Morris, JS; Thearle, DJ; Jensen, KP; Kay, TWH; Rossjohn, J; Falk, BA; Nepom, GT; Purcell, AW
2005-11-07
JOURNAL OF EXPERIMENTAL MEDICINE
Journal Article
202
9
1191-1197
The autoimmune process that destroys the insulin-producing pancreatic beta 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.
ROCKEFELLER UNIV PRESS
DIABETES-MELLITUS; HUMAN THYMUS; NOD MICE; AUTOANTIGEN; PROINSULIN; EXPRESSION; LOCUS; SUSCEPTIBILITY; IDDM2; MOUSE
10.1084/jem.20051251
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Creation Date 2005-11-07 12:00:00