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

• Published in: Molecular immunology 2007-04, Vol.44 (11), p.2950-2960
• Main Authors: Severe, Sabine, Gauvrit, Anne, Vu, Anh-Tuan, Bach, Jean-Marie
• Format: Article
• Language: English
• ISSN: 0161-5890
• DOI: 10.1016/j.molimm.2007.01.008

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 super(+) T cells, and no diabetogenic CD8 super(+) 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 super(+) T cell epitope (GAD sub(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 naive female NOD mice, CD8 super(+) T lymphocytes recognizing GAD sub(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 sub(90-98) specific CD8 super(+) lymphocytes lysed efficiently islet cells in vitro and transferred diabetes into NOD super(SCID) mice (100%). Finally, diabetes was accelerated greatly in 3-week- old female NOD mice injected i.p. with GAD sub(90-98), strengthening the role of GAD-specific CTLs in diabetes pathogenesis.