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.
Sévère
Sabine
S
Immuno-endocrinology Unit, ENVN/INRA/University, Atlanpôle-La Chantrerie, BP 40706, 44307 Nantes Cedex 03, France.
Gauvrit
Anne
A
Vu
Anh-Tuan
AT
Bach
Jean-Marie
JM
D000818:Animals; D017951:Antigen Presentation; D015551:Autoimmunity; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology*; D003922:Diabetes Mellitus, Type 1 / Q000276:immunology*; D018984:Epitopes, T-Lymphocyte / Q000276:immunology*; D005260:Female; D005968:Glutamate Decarboxylase / Q000276:immunology*; D006801:Humans; D007114:Immunization; D051379:Mice; D016688:Mice, Inbred NOD; D010446:Peptide Fragments / Q000276:immunology; D016176:T-Lymphocyte Subsets / Q000276:immunology
D018984:Epitopes, T-Lymphocyte; D010446:Peptide Fragments; D005968:Glutamate Decarboxylase