title: The A-chain of insulin is a hot-spot for CD4+ T cell epitopes in human type 1 diabetes.
abstract: 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.
authors.affiliation: Autoimmunity and Transplantation Division, The Walter and Eliza Hall Institute of Medical Research, 1G Royal Parade, Parkville, Australia. smannering@svi.edu.au
authors.forename: S I
authors.initials: SI
authors.lastname: Mannering
authors.forename: S H
authors.initials: SH
authors.lastname: Pang
authors.forename: N A
authors.initials: NA
authors.lastname: Williamson
authors.forename: G
authors.initials: G
authors.lastname: Naselli
authors.forename: E C
authors.initials: EC
authors.lastname: Reynolds
authors.forename: N M
authors.initials: NM
authors.lastname: O'Brien-Simpson
authors.forename: A W
authors.initials: AW
authors.lastname: Purcell
authors.forename: L C
authors.initials: LC
authors.lastname: Harrison
mesh_terms: D017951:Antigen Presentation; D002096:C-Peptide / Q000737:chemistry; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology*; D003545:Cysteine / Q000737:chemistry; D003922:Diabetes Mellitus, Type 1 / Q000276:immunology*; D018604:Epitope Mapping; D018984:Epitopes, T-Lymphocyte / Q000737:chemistry / Q000276:immunology*; D015804:HLA-DR4 Antigen / Q000276:immunology; D006801:Humans; D007328:Insulin / Q000737:chemistry / Q000276:immunology*; D011384:Proinsulin / Q000737:chemistry / Q000276:immunology; D011948:Receptors, Antigen, T-Cell / Q000276:immunology
chemical_list: D002096:C-Peptide; D018984:Epitopes, T-Lymphocyte; D015804:HLA-DR4 Antigen; D007328:Insulin; D011948:Receptors, Antigen, T-Cell; D011384:Proinsulin; D003545:Cysteine