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.
Highlights
The initial event leading to type 1 diabetes remains elusive, many data converge, both in mice and in humans, to establish that T cell-mediated autoimmunity toward several pancreatic islet cell autoantigens plays a significant role in pathogenesis [1, 2]
Synthetic peptides encompassing a GAD65 class Insulitis index (II)-restricted epitope (e.g., GAD65528–538, KVAPVIKARMM reported as WTGAD65), the same epitope containing a thioreductase motif of the CxxC format, wherein C stands for cysteine and x for any amino acid in flanking residues, the lossof-function sequence where the CxxC motif is replaced by a AxxA motif, wherein A stands for alanine, a non-relevant hen egg lysozyme (HEL) class II-restricted epitope (NTDGSTDYGILQINSR reported as WTHEL), and the CxxC-containing counterpart were produced by solid phase Fmoc chemistry (Eurogentec, Liège, Belgium)
Four-week-old female non-obese diabetes (NOD) mice were immunized with a peptide encompassing a class II-restricted GAD65 epitope and a thioreductase motif (CCGAD65) in conventional animal facilities
Summary
The initial event leading to type 1 diabetes remains elusive, many data converge, both in mice and in humans, to establish that T cell-mediated autoimmunity toward several pancreatic islet cell autoantigens plays a significant role in pathogenesis [1, 2]. Numerous studies have demonstrated the efficacy of antigen-based therapies, including GAD65 protein, peptides, or modified peptides, in preventing type 1 diabetes in non-obese diabetes (NOD) mice [6]. These strategies are based either on a shift within CD4+ cells from a Th1 to a Th2 profile or on the induction of tolerance by the activation of regulatory T cells (Tregs).
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