Constitutive expression of the NKG2D ligand RAE1ɛ within pancreatic islets ameliorates autoimmune diabetes development in non-obese diabetic mice

Abstract

Abstract Type 1, or autoimmune, diabetes is driven by T cell-mediated destruction of the insulin-producing β cells in pancreatic islets. The natural killer cell activating receptor NKG2D and its ligands are implicated in this process. However, the mechanism by which NKG2D-NKG2D ligand interaction affects diabetes development is poorly understood. Transgenic expression of the NKG2D ligand retinoic acid early transcript 1ɛ (RAE1ɛ) in β-islet cells of the pancreas induces the recruitment of cytotoxic T lymphocytes (CTLs) to the islets in mice. Surprisingly, however, we report here that the severity of spontaneous autoimmune diabetes is decreased in non-obese diabetic (NOD) mice expressing RAE1ɛ in islets (RIP-RAE1ɛ NOD). Interestingly, NKG2D expression is reduced on the surface of CD8T cells within the pancreas of RIP-RAE1ɛ NOD mice compared with control NOD mice. We further demonstrate that the NKG2D ligand H60a is expressed on T cells within the pancreas of wild-type NOD mice. Together, these results demonstrate that transgenic expression of RAE1ɛ in islets leads to down-regulation of NKG2D surface expression on CD8T cells, likely resulting in decreased ability of the cells to respond to NKG2D engagement by H60a naturally expressed in the pancreas. These findings suggest that interaction between NKG2D and NKG2D ligands, both expressed on islet-infiltrating T cells, plays an important role in the pathology associated with autoimmune diabetes.