title: T cells recognize multiple GAD65 and proinsulin epitopes in human type 1 diabetes, suggesting determinant spreading.
abstract: Human type 1 diabetes is thought to be mediated by autoreactive T cells specific for antigens expressed by pancreatic beta cells. However, it is unclear which autoantigens and determinants thereof are the targets of the autoimmune attack. Using comprehensive peptide libraries that cover the entire sequence of two major candidate autoantigens, GAD65 and proinsulin, we measured the in vivo frequencies of peptide-specific, IFN-gamma-producing memory T cells in 27 diabetic patients, 14 high risk individuals, and 15 partially HLA-matched healthy controls. Compared to the controls, both a higher number of determinants on the islet cell antigens were recognized and the frequencies of peptide specific cells were increased in patients and high risk individuals. Inclusion of signal enhancing anti-CD28 antibody further accentuated this difference. Considerable heterogeneity in peptide recognition was seen even in DRB1*04, DQB1*0302 matched individuals. Unlike its peptides, the GAD protein antigen did not recall a T cell memory response. The highly heterogeneous recognition of a multitude of peptide determinants on both autoantigens, occurring in the absence of protein recognition, and the low functional avidity of the memory cells involved jointly suggest that the autoimmune T cell repertoire in human type 1 diabetes primarily targets cryptic determinants engaged by determinant spreading.
authors.affiliation: Department of Pathology, Case Western Reserve University, BRB 929, 10900 Euclid Avenue, Cleveland, Ohio 44116, USA.
authors.forename: Patrick A
authors.initials: PA
authors.lastname: Ott
authors.forename: Marcus T
authors.initials: MT
authors.lastname: Dittrich
authors.forename: Bernhard A
authors.initials: BA
authors.lastname: Herzog
authors.forename: Robert
authors.initials: R
authors.lastname: Guerkov
authors.forename: Peter A
authors.initials: PA
authors.lastname: Gottlieb
authors.forename: Amy L
authors.initials: AL
authors.lastname: Putnam
authors.forename: Ivana
authors.initials: I
authors.lastname: Durinovic-Bello
authors.forename: Bernhard O
authors.initials: BO
authors.lastname: Boehm
authors.forename: Magdalena
authors.initials: M
authors.lastname: Tary-Lehmann
authors.forename: Paul V
authors.initials: PV
authors.lastname: Lehmann
mesh_terms: D000940:Antigenic Variation; D001324:Autoantigens / Q000276:immunology; D016022:Case-Control Studies; D003922:Diabetes Mellitus, Type 1 / Q000276:immunology*; D000939:Epitopes / Q000276:immunology; D005968:Glutamate Decarboxylase / Q000276:immunology*; D006650:Histocompatibility Testing; D006801:Humans; D007156:Immunologic Memory; D007527:Isoenzymes / Q000276:immunology*; D018655:Lymphocyte Count; D010446:Peptide Fragments / Q000276:immunology; D011384:Proinsulin / Q000276:immunology*; D016176:T-Lymphocyte Subsets / Q000166:cytology / Q000276:immunology; D013601:T-Lymphocytes / Q000276:immunology*
chemical_list: D001324:Autoantigens; D000939:Epitopes; D007527:Isoenzymes; D010446:Peptide Fragments; D011384:Proinsulin; D005968:Glutamate Decarboxylase; C401141:glutamate decarboxylase 2