The insulin A-chain epitope recognized by human T cells is posttranslationally modified.
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.
Mannering
Stuart I
SI
Autoimmunity and Transplantation Division, The Walter and Eliza Hall Institute of Medical Research, Royal Melbourne Hospital, Parkville, Victoria, Australia. mannering@wehi.edu.au
Harrison
Leonard C
LC
Williamson
Nicholas A
NA
Morris
Jessica S
JS
Thearle
Daniel J
DJ
Jensen
Kent P
KP
Kay
Thomas W H
TW
Rossjohn
Jamie
J
Falk
Ben A
BA
Nepom
Gerald T
GT
Purcell
Anthony W
AW
D002478:Cells, Cultured; D003545:Cysteine / Q000276:immunology / Q000378:metabolism; D018604:Epitope Mapping; D018984:Epitopes, T-Lymphocyte / Q000235:genetics / Q000276:immunology* / Q000378:metabolism*; D015804:HLA-DR4 Antigen / Q000378:metabolism; D006801:Humans; D007328:Insulin / Q000235:genetics / Q000276:immunology* / Q000378:metabolism*; D008297:Male; D010084:Oxidation-Reduction; D011499:Protein Processing, Post-Translational; D021122:Protein Subunits / Q000235:genetics / Q000276:immunology* / Q000378:metabolism*; D013601:T-Lymphocytes / Q000276:immunology* / Q000378:metabolism
D018984:Epitopes, T-Lymphocyte; D015804:HLA-DR4 Antigen; D007328:Insulin; D021122:Protein Subunits; D003545:Cysteine