Diabetes Autoantigens of Potential Clinical Relevance Humanized NOD Mice Recognize HLA - A * 0201 - Restricted T Cells from

In both humans and NOD mice, particular MHC genes are primary contributors to development of the autoreactive CD4 ؉ and CD8 ؉ T cell responses against pancreatic ␤ cells that cause type 1 diabetes (T1D). Association studies have suggested, but not proved, that the HLA-A*0201 MHC class I variant is an important contributor to T1D in humans. In this study, we show that transgenic expression in NOD mice of HLA-A*0201, in the absence of murine class I MHC molecules, is sufficient to mediate autoreactive CD8 ؉ T cell responses contributing to T1D development. CD8 ؉ T cells from the transgenic mice are cytotoxic to murine and human HLA-A*0201-positive islet cells. Hence, the murine and human islets must present one or more peptides in common. Islet-specific glucose-6-phosphatase catalytic subunit-related protein (IGRP) is one of several important T1D autoanti-gens in standard NOD mice. Three IGRP-derived peptides were identified as targets of diabetogenic HLA-A*0201-restricted T cells in our NOD transgenic stock. Collectively, these results indicate the utility of humanized HLA-A*0201-expressing NOD mice in the identification of T cells and autoantigens of potential relevance to human T1D. In particular, the identified antigenic peptides represent promising tools to explore the potential importance of IGRP in the development of human T1D. T ype 1 diabetes (T1D) 5 in both humans and NOD mice is a multifactorial disease resulting from T cell-mediated au-toimmune destruction of insulin-secreting pancreatic ␤ cells. Although T1D is a polygenic disease, the primary susceptibility component in both organisms is particular combinations of MHC genes (reviewed in Refs. 1 and 2). Within the MHC, specific HLA-DQ and HLA-DR class II molecules provide a large component of T1D susceptibility in humans by mediating ␤ cell-au-toreactive CD4 ϩ T cell responses. Similarly, the H-2A g7 class II variant provides an important component of T1D susceptibility in NOD mice. It is now clear that in addition to the pathogenic effects mediated by CD4 ϩ T cells, T1D development also requires contributions from autoreactive MHC class I-restricted CD8 ϩ T cells (3– 8). Interestingly, the H-2D b and H-2K d class I molecules encoded within the H2 g7 MHC haplotype of NOD mice are common variants also characterizing many strains lacking autoimmune proclivity. However, efficient T1D development in NOD mice is dependent on expression of the class I genes characterizing the H2 g7 haplotype (9 –12). The ability of the H2 g7-encoded class I variants to mediate the …