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Diabetes 54:92-99, 2005
© 2005 by the American Diabetes Association, Inc.

Defective Suppressor Function in CD4+CD25+ T-Cells From Patients With Type 1 Diabetes

Shelley Lindley1, Colin M. Dayan2, Amanda Bishop2, Bart O. Roep3, Mark Peakman1, and Timothy I.M. Tree1

1 Department of Immunobiology, Guy’s, King’s & St Thomas’ School of Medicine, King’s College London, U.K
2 Bristol Royal Infirmary, Bristol, U.K
3 Department of Immunohaematology & Blood Transfusion, Leiden University Medical Center, Leiden, The Netherlands

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.

Address correspondence and reprint requests to Timothy I.M. Tree, Department of Immunobiology, Guy’s, King’s & St Thomas’ School of Medicine, 2nd Floor, New Guy’s House, Guy’s Hospital London SE1 9RT, U.K. E-mail: timothy.tree{at}kcl.ac.uk


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