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The development of autoimmune diabetes in both humans and nonobese diabetic (NOD) mice is highly influenced by specific alleles of the class II MHC genes: HLA-DQ2 and HLA-DQ8 in humans and I-Ag7 in mice (Acha-Orbea and McDevitt, 1987; Cucca et al., 2001). CD4+ T cells are essential in initiating the autoim-mune response and, consequently, much empha-sis has been placed on deciphering the relevant self-peptides recognized by these cells driving the development of diabetes (Anderson and Bluestone, 2005). The work of many laboratories has empha-sized the importance of insulin as a critical tar-get of the immune response for the development of autoimmune diabetes (Zhang et al., 2008). Extensive analysis of the T cell response directed against insulin has highlighted an immunodomi-nant segment of the insulin B chain, the B:9-23 (SHLVEALYLVCGERG) peptide (Wegmann et al., 1994a,1994b; Daniel et al., 1995; Abiru et al., 2001; Halbout et al., 2002). CD4+ T cells recognizing B:9-23 are detected within the infil-trated islets of prediabetic mice and antigenic masking of this epitope via mutation or tolero-genic expression in APCs diminished islet auto-immunity, signifying the essential role recognition of the B:9-23 epitope in the development of dia-betes (French et al., 1997; Jaeckel et al., 2004; Nakayama et al., 2005). These studies and others convincingly show that insulin is among the fore-most targets in NOD diabetes, and its recogni-tion by CD4+ T cells likely initiates a cascade of downstream events driving both the amplifi-cation and diversification of the autoimmune response, ultimately resulting in the complete destruction of cells (Nakayama et al., 2007; Krishnamurthy et al., 2008). As a result, much importance has been placed on understandin