CD8+ T lymphocytes specific for glutamic acid decarboxylase 90-98 epitope mediate diabetes in NOD SCID mouse.

During the past decade, glutamic acid decarboxylase (GAD) has been considered a crucial beta-cell autoantigen involved in type 1 diabetes in the NOD mouse and human. Recently, the etiological role of GAD has remained controversy. In the NOD mouse, some previous studies argued in favor of a regulatory role for GAD-specific CD4+ T cells, and no diabetogenic CD8+ T cells specific for GAD have been identified so far, discrediting the importance of GAD in beta-cell injury. Here, we identified, in the NOD model, a relevant GAD CD8+ T cell epitope (GAD(90-98)) using immunization with a plasmid encoding GAD, a protocol relying on in vivo processing of peptides from the autoantigenic protein. In pancreatic lymph nodes of naïve female NOD mice, CD8+ T lymphocytes recognizing GAD(90-98) peptide were detected during the initial phase of invasive insulitis (between 4 and 8 weeks of age), suggesting an important role for these cells in the first stage of the disease. GAD(90-98) specific CD8+ lymphocytes lysed efficiently islet cells in vitro and transferred diabetes into NOD(SCID) mice (100%). Finally, diabetes was accelerated greatly in 3-week-old female NOD mice injected i.p. with GAD(90-98), strengthening the role of GAD-specific CTLs in diabetes pathogenesis.