title: Defective suppressor function in CD4(+)CD25(+) T-cells from patients with type 1 diabetes.
abstract: Type 1 diabetes is a T-cell-mediated disease that is associated with loss of immunological tolerance to self-antigens. The mechanisms involved in maintenance of peripheral tolerance include a specialized subset of regulatory T-cells (Treg) within the CD4(+)CD25(+) T-cell population, but the function and phenotype of these cells in type 1 diabetes have not been investigated. We hypothesized that a deficiency in the CD4(+)CD25(+) Treg population or its function could contribute to the lack of self-tolerance evident in patients with type 1 diabetes. We show that although levels of CD4(+)CD25(+) T-cells are normal in patients with recent-onset adult type 1 diabetes, the ability of the Tregs in this population to suppress T-cell proliferation during in vitro cocultures is markedly reduced compared with control subjects (P = 0.007). Moreover, in patients with type 1 diabetes, these cocultures display a more proinflammatory phenotype, with increased secretion of interferon-gamma (P = 0.005) and decreased interleukin-10 production (P = 0.03). These deficiencies may reflect a disturbance in the balance of the CD4(+)CD25(+) population, because in patients with type 1 diabetes, a higher proportion of these cells coexpress the early activation marker CD69 (P = 0.007) and intracellular CTLA-4 (P = 0.01). These data demonstrate deficiency in function of the CD4(+)CD25(+) Treg population that may influence the pathogenesis of type 1 diabetes.
authors.affiliation: Department of Immunobiology, Guy's, King's and St Thomas' School of Medicine, 2nd Floor, New Guy's House, Guy's Hospital London SE1 9RT, UK.
authors.forename: Shelley
authors.initials: S
authors.lastname: Lindley
authors.forename: Colin M
authors.initials: CM
authors.lastname: Dayan
authors.forename: Amanda
authors.initials: A
authors.lastname: Bishop
authors.forename: Bart O
authors.initials: BO
authors.lastname: Roep
authors.forename: Mark
authors.initials: M
authors.lastname: Peakman
authors.forename: Timothy I M
authors.initials: TI
authors.lastname: Tree
mesh_terms: D000328:Adult; D015703:Antigens, CD / Q000276:immunology*; D000943:Antigens, Differentiation / Q000276:immunology; D015704:CD4 Antigens / Q000276:immunology*; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology*; D060908:CTLA-4 Antigen; D003922:Diabetes Mellitus, Type 1 / Q000276:immunology*; D005260:Female; D006801:Humans; D008213:Lymphocyte Activation; D008297:Male; D015375:Receptors, Interleukin-2 / Q000276:immunology*; D012016:Reference Values; D050378:T-Lymphocytes, Regulatory / Q000276:immunology*
chemical_list: D015703:Antigens, CD; D000943:Antigens, Differentiation; D015704:CD4 Antigens; D060908:CTLA-4 Antigen; C556706:CTLA4 protein, human; D015375:Receptors, Interleukin-2