title: Thioreductase-Containing Epitopes Inhibit the Development of Type 1 Diabetes in the NOD Mouse Model.
abstract: Autoreactive CD4(+) T cells recognizing islet-derived antigens play a primary role in type 1 diabetes. Specific suppression of such cells therefore represents a strategic target for the cure of the disease. We have developed a methodology by which CD4(+) T cells acquire apoptosis-inducing properties on antigen-presenting cells after cognate recognition of natural sequence epitopes. We describe here that inclusion of a thiol-disulfide oxidoreductase (thioreductase) motif within the flanking residues of a single MHC class II-restricted GAD65 epitope induces GAD65-specific cytolytic CD4(+) T cells (cCD4(+) T). The latter, obtained either in vitro or by active immunization, acquire an effector memory phenotype and lyse APCs by a Fas-FasL interaction. Furthermore, cCD4(+) T cells eliminate by apoptosis activated bystander CD4(+) T cells recognizing alternative epitopes processed by the same APC. Active immunization with a GAD65 class II-restricted thioreductase-containing T cell epitope protects mice from diabetes and abrogates insulitis. Passive transfer of in vitro-elicited cCD4(+) T cells establishes that such cells are efficient in suppressing autoimmunity. These findings provide strong evidence for a new vaccination strategy to prevent type 1 diabetes.
authors.affiliation: Center for Molecular and Vascular Biology, University of Leuven, Leuven, Belgium; ImCyse SA, Leuven, Belgium.
authors.forename: Elin
authors.initials: E
authors.lastname: Malek Abrahimians
authors.affiliation: Center for Molecular and Vascular Biology, University of Leuven, Leuven, Belgium; ImCyse SA, Leuven, Belgium.
authors.forename: Luc
authors.initials: L
authors.lastname: Vander Elst
authors.affiliation: Center for Molecular and Vascular Biology, University of Leuven, Leuven, Belgium; ImCyse SA, Leuven, Belgium.
authors.forename: Vincent A
authors.initials: VA
authors.lastname: Carlier
authors.affiliation: Center for Molecular and Vascular Biology, University of Leuven, Leuven, Belgium; ImCyse SA, Leuven, Belgium.
authors.forename: Jean-Marie
authors.initials: JM
authors.lastname: Saint-Remy
keywords: MHC class II epitopes; NOD mouse; antigen-specific; cytolytic CD4+ T cells; type 1 diabetes