Abstract
Type 1 diabetes (T1D) is an autoimmune disease in which destruction of insulin-producing β-cells leads to dependence on exogenous insulin (1). T1D progression involves progressive loss of tolerance to β-cell antigens, but this has been challenging to observe in human disease. Loss of self-tolerance is most evident through development of islet cell antibodies, among which insulin antibodies typically appear first (2). Given strong genetic association of T1D with HLA-DQ8, DQ8-restricted CD4+ T cells activated by self-peptides are thought to play a crucial role in disease. Key evidence from the nonobese diabetic (NOD) mouse model supports a primary role for recognition of an epitope within the insulin B chain amino acids 9–23 (InsB9–23) peptide in disease initiation. The majority of CD4+ T cells isolated from pancreatic islets of NOD mice were shown to respond to this peptide (3). Furthermore, expression of an insulin transgene with a substitution within this peptide abrogated diabetes development (4). Efforts to directly visualize and study insulin-specific T cells in human subjects have been hampered by the biochemical instability of the HLA-DQ8 protein (5). However, recent reports highlight the development of HLA-DQ8 tetramer reagents and their application to study T1D, affirming that InsB11–23 peptide is analogously presented by IAg7 and HLA-DQ8 (6,7). In addition, two recent reports documented the presence …
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