Autoimmune Type 1 diabetes (T1D) is the result of T cell mediated destruction of the insulin secreting pancreatic beta-cells. While unusual MHC class II alleles contribute to T1D susceptibility, it has become clear that MHC class I restricted CD8 T cells are critical for initiation of the autoimmune response. Therefore, if tolerogenic protocols to prevent T1D in human patients are to be developed, it is important to identify the antigens that are recognized by beta-cell autoreactive CD8 T cells. These studies are not possible in human patients. However, through the use of NOD mice transgenically expressing human MHC class I molecules, it may be possible to identify antigens with clinical relevance to human patients. Epidemiological studies have indicated that, although common, the MHC class I alleles HLA-A2 and HLA-A24 can lead to increased T1D susceptibility and earlier age of disease onset when expressed in conjunction with high-risk class II alleles. Preliminary studies have demonstrated significant acceleration of T1D in NOD mice transgenically expressing HLA-A2.1 molecules. Other data indicate T1D continues to develop in a genetically engineered NOD stock in which the only type of MHC class I molecules expressed is the human HLA-A2.1 variant. These results indicate HLA-A2.1 molecules can mediate diabetogenic CD8 T cell responses critical for the initiation of T1D even in the absence of murine MHC class I molecules. Given these results, NOD stocks transgenically expressing HLA-A2.1 molecules should serve as excellent models for understanding the nature of the pathogenic CD8 T cell response in humans and the autoantigens that are being recognized during the initiation phase of the disease. Supporting this approach are previous studies which have demonstrated that the panel of antigenic peptides presented by transgenically expressed HLA-A2.1 molecules in mice overlaps the panel of peptides presented by endogenous HLA-A2.1 molecules in humans. Additionally, conservation of beta-cell proteins implicated in T1D pathogenesis suggests that the antigenic peptides identified in transgenic mice will provide insight into autoantigens presented by these class 1 molecules in humans. Therefore my first aim is to determine the breadth of diabetogenic CD8 T cell clonotypes elicited by HLA-A2.1 molecules transgenically expressed in NOD mice. While NOD mice transgenically expressing HLA-A2.1 molecules show significantly accelerated onset of T1D, in humans HLA-A24 is even more strongly associated with increased susceptibility. Thus, my second specific aim is to determine if the range of diabetogenic CD8 T cell clonotypes elicited by transgenic expression of HLA-A24 molecules is more diverse than that elicited by HLA-A2.1 molecules.
| Jarchum, Irene; Baker, Jason C; Yamada, Tatsuya et al. (2007) In vivo cytotoxicity of insulin-specific CD8+ T-cells in HLA-A*0201 transgenic NOD mice. Diabetes 56:2551-60 |
| Takaki, Toshiyuki; Marron, Michele P; Mathews, Clayton E et al. (2006) HLA-A*0201-restricted T cells from humanized NOD mice recognize autoantigens of potential clinical relevance to type 1 diabetes. J Immunol 176:3257-65 |
