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Coexpression of CD25 and OX40 (CD134) Receptors Delineates Autoreactive T-cells in Type 1 Diabetes

¹ Roche Diagnostics, Penzberg, Germany
² Division of Endocrinology and Diabetes, Department of Internal Medicine, Ulm University, Ulm, Germany
³ Institute for Clinical Chemistry and Laboratory Medicine, University of Regensburg, Regensburg, Germany
⁴ Institute of Pathophysiology, Ernst Moritz Arndt University of Greifswald, Greifswald, Germany
⁵ Department of Transfusion Medicine and Bone Marrow Transplantation Center, University Hospital Eppendorf, Hamburg, Germany
⁶ Institute of Molecular Immunology, GSF-National Research Center for Environment and Health, Munich, Germany

Address correspondence and reprint requests to Prof. Bernhard O. Boehm, MD, Division of Endocrinology and Diabetes, Ulm, University, Robert-Koch-Str. 8, D-89081 Ulm, Germany. E-mail: bernhard.boehm{at}medizin.uni-ulm.de

Abbreviations: APC, antigen-presenting cell; FACS, fluorescence-activated cell sorter; IA-2, insulinoma-associated protein 2; ICA, islet cell autoantibody; IL-2, interleukin-2; mAb, monoclonal antibody; PBMC, peripheral blood mononuclear cell; PPI, preproinsulin; TT, tetanus toxoid

T-cell–mediated loss of pancreatic ß-cells is the crucial event in the development of type 1 diabetes. The phenotypic characteristics of disease-associated T-cells in type 1 diabetes have not yet been defined. The negative results from two intervention trials (the Diabetes Prevention Trial–Type 1 Diabetes and the European Nicotinamide Diabetes Intervention Trial) illustrate the need for technologies to specifically monitor ongoing autoimmune reactions. We used fluorescence-activated cell sorter analysis to study surface marker expression on T-cell lines specific for two major type 1 diabetes autoantigens, GAD65 and proinsulin. We then applied this knowledge in a cross-sectional approach to delineate the phenotype of circulating memory T-cells. The autoreactive T-cells of patients could be distinguished from those of control subjects by their coexpression of CD25 and CD134. Autoantigen-specific T-cells that recognized multiple GAD65- and preproinsulin-derived peptides and coexpressed CD25⁺CD134⁺ were confined to patients (n = 32) and pre-diabetic probands (n = 5). Autoantigen-reactive T-cells in control subjects (n = 21) were CD25⁺CD134^– and recognized fewer autoantigen-derived peptides. Insulin therapy did not induce CD25⁺CD134⁺ T-cells in type 2 diabetic patients. The coexpression of CD25 and the costimulatory molecule CD134 on memory T-cells provides a novel marker for type 1 diabetes–associated T-cell immunity. The CD134 costimulatory molecule may also provide a novel therapeutic target in type 1 diabetes.

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