The selection of MHC class I-restricted T cell responses to GAD65 in autoimmune diabetes

Type 1 diabetes (T1D) is a T cell mediated organ-specific autoimmune disease characterized by the selective destruction of insulin-producing beta cells of the pancreas. T1D affects 2.8 Million people in the USA, with annual health care expenditure in the billions of dollars. This disorder mainly affects children and young adults and no known prevention or cure is currently available. A central topic of this study is the initial assault that leads to inflammation in the islets and T1D development. Many studies support the involvement of CD4 T cells in the pathogenesis of T1D. CD8 T cells have also been linked to the development of T1D, but less is known about their contribution. Immune responses to several autoantigens have been correlated with the development of T1D but none have been found to elicit a spontaneous immune response at an earlier time point than glutamic acid decarboxylase 65 (GAD65). Immune responses to GAD65 are associated with the progression of T1D in both the murine model and humans. GAD65 induces both CD4 and CD8 T cell responses prior to the onset of T1D. Previous studies have shown that GAD65 responsive CD8 T cells are found in prediabetic NOD mice and also in peripheral blood of recently diagnosed humans. Since CD8 T cell responses may initiate the earliest stages of autoimmune diabetes, it is important to characterize the CD8 T cell response to GAD65 in order to understand its role in the development of disease. To identify determinants of GAD65 that are associated with autoimmunity in the NOD mouse model, a peptide scan of GAD65 was used, identifying a pathogenic MHC class-I determinant. MHC class-I (cytoplasmic) and MHC class-II (vesicular) pathways of epitope production have been looked at in professional antigen presenting cells identifying a TAP-independent pathway for MHC class-I presentation. Finally, the GAD65 determinant eliciting a pathogenic response in the NOD mouse model was assessed in the NOD.HLA-A2 murine model illustrating that this pathogenic MHC class-I determinant is also relevant in a humanized murine model of autoimmune diabetes. These results confirm that GAD65 is a relevant autoantigen in T1D in both NOD mice and humans and that further study of GAD65 as it relates to T1D is warranted.