NF-κB is weakly activated in the NOD mouse model of type 1 diabetes.

Type 1 diabetes is an autoimmune disease characterised by selective destruction of pancreatic beta cells by the immune system. The transcription factor nuclear factor-kappa B (NF-κB) regulates innate and adaptive immune responses. Using gene targeting and in vitro analysis of pancreatic islets and immune cells, NF-κB activation has been implicated in type 1 diabetes development. Here we use a non-obese diabetic (NOD) mouse model that expresses a luciferase reporter of transcriptionally active NF-κB to determine its activation in vivo during development of diabetes. Increased luciferase activity was readily detected upon treatment with Toll-like receptor ligands in vitro and in vivo, indicating activation of NF-κB. However, activated NF-κB was detectable at low levels above background in unmanipulated NOD mice, but did not vary with age, despite the progression of inflammatory infiltration in islets over time. NF-κB was highly activated in an accelerated model of type 1 diabetes that requires CD4+ T cells and inflammatory macrophages. These data shed light on the nature of the inflammatory response in the development of type 1 diabetes.

An indirect role for NK cells in a CD4(+) T-cell-dependent mouse model of type I diabetes.

CD8(+) T cells kill pancreatic ß-cells in a cell-cell contact-dependent mechanism in the non-obese diabetic mouse. CD4(+) T lymphocytes are also able to kill pancreatic ß-cells, but they do not directly contact ß-cells and may use another cell type as the actual cytotoxic cell. Natural killer (NK) cells could have this role but it is uncertain whether they are cytotoxic towards ß-cells. Therefore, the requirement for NK cells in ß-cell destruction in the CD4-dependent T-cell antigen receptor transgenic NOD4.1 mice was examined. NK cells failed to kill ß-cells in vitro, even in the absence of major histocompatibility complex class I. We observed only 9.7±1.1% of islet infiltrating NK cells from NOD4.1 mice expressing the degranulation marker CD107a. Diabetogenic CD4(+) T cells transferred disease to NODscid.IL2Rγ(-/-) mice lacking NK cells, indicating that NK cells do not contribute to ß-cell death in vitro or in vivo. However, depletion of NK cells reduced diabetes incidence in NOD4.1 mice, suggesting that NK cells may help to maintain the right environment for cytotoxicity of effector cells.