title: Coexpression of CD25 and OX40 (CD134) receptors delineates autoreactive T-cells in type 1 diabetes.
abstract: T-cell-mediated loss of pancreatic beta-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.
authors.affiliation: Division of Endocrinology and Diabetes, Ulm University, Robert-Koch-Strasse 8, D-89081 Ulm, Germany.
authors.forename: Josef
authors.initials: J
authors.lastname: Endl
authors.forename: Silke
authors.initials: S
authors.lastname: Rosinger
authors.forename: Barbara
authors.initials: B
authors.lastname: Schwarz
authors.forename: Sven-Olaf
authors.initials: SO
authors.lastname: Friedrich
authors.forename: Gregor
authors.initials: G
authors.lastname: Rothe
authors.forename: Wolfram
authors.initials: W
authors.lastname: Karges
authors.forename: Michael
authors.initials: M
authors.lastname: Schlosser
authors.forename: Thomas
authors.initials: T
authors.lastname: Eiermann
authors.forename: Dolores J
authors.initials: DJ
authors.lastname: Schendel
authors.forename: Bernhard O
authors.initials: BO
authors.lastname: Boehm
mesh_terms: D015551:Autoimmunity / Q000276:immunology*; D015415:Biomarkers; D002460:Cell Line; D003922:Diabetes Mellitus, Type 1 / Q000235:genetics / Q000276:immunology* / Q000473:pathology*; D005260:Female; D005786:Gene Expression Regulation; D006801:Humans; D008213:Lymphocyte Activation; D008297:Male; D015375:Receptors, Interleukin-2 / Q000235:genetics / Q000378:metabolism*; D053262:Receptors, OX40; D018124:Receptors, Tumor Necrosis Factor / Q000235:genetics / Q000378:metabolism*; D013601:T-Lymphocytes / Q000276:immunology* / Q000473:pathology*; D015854:Up-Regulation
chemical_list: D015415:Biomarkers; D015375:Receptors, Interleukin-2; D053262:Receptors, OX40; D018124:Receptors, Tumor Necrosis Factor; C505716:TNFRSF4 protein, human