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

• Published in: Molecular immunology Vol. 44; no. 11; pp. 2950 - 2960
• Main Authors: Sévère, Sabine, Gauvrit, Anne, Vu, Anh-Tuan, Bach, Jean-Marie
• Format: Journal Article
• Language: English
• Published: Elsevier 01.04.2007
• Subjects: Immunology; Life Sciences; C T CELL; ANTIGENS/PEPTIDES/EPITOPES; AUTOIMMUNITY; DIABETES; MOLECULAR BIOLOGY
• ISSN: 0161-5890
• DOI: 10.1016/j.molimm.2007.01.008

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 (GAD90–98) 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 GAD90–98 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. GAD90–98 specific CD8+ lymphocytes lysed efficiently islet cells in vitro and transferred diabetes into NODSCID mice (100%). Finally, diabetes was accelerated greatly in 3-week-old female NOD mice injected i.p. with GAD90–98, strengthening the role of GAD-specific CTLs in diabetes pathogenesis.