The good turned ugly: Immunopathogenic basis for diabetogenic CD8 ⁺ T cells in NOD mice

Type 1 diabetes (T1D) in both humans and nonobese diabetic (NOD) mice is a T-cell-mediated autoimmune disease in which the insulin-producing pancreatic islet β-cells are selectively eliminated. As a result, glucose metabolism cannot be regulated unless exogenous insulin is administered. Both the CD4 ⁺ and the CD8⁺ T-cell subsets are required for TD development. Approximately 20 years ago, an association between certain class II major histocompatibility complex (MHC) alleles and susceptibility to T1D was reported. This finding led to enormous interest in the CD4⁺ T cells participating in the development of T1D, while the CD8⁺ subset was relatively ignored. However, the isolation of β-cell-autoreactive CD8 ⁺ T-cell clones from the islets of NOD mice helped to generate interest in the pathogenic role of this subset, as has accumulating evidence that certain class I MHC alleles are additional risk factors for T1D development in humans. Three distinct diabetogenic CD8⁺ T-cell populations have now been characterized in NOD mice. Here, we review recent investigations exploring their selection, activation, trafficking, and antigenic specificities. As CD8⁺ T cells are suspected contributors to β-cell demise in humans, continued exploration of these critical areas could very possibly lead to tangible benefits for T1D patients and at-risk individuals.