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

Abstract

During the past decade, glutamic acid decarboxylase (GAD) has been considered a crucial β-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 β-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.