Grant: Operating Grant

Type 1 diabetes (T1D) results from immune dysregulation (autoimmunity) leading to destruction of the insulin-producing cells of the pancreas (beta cells) by killer white blood cells. Susceptibility to T1D is genetically determined, but the mechanisms are poorly understood. Our studies to date have explored mechanisms underlying the genetic risk to T1D afforded by 3 different genes, and have discovered that all 3 affect the development and function of a type of white blood cell whose job is to protect us against T1D ('suppressor cells'). Particularly significant with regards to human T1D are our studies of the mouse 'Interleukin 2' gene. Like its mouse counterpart, the human Interleukin 2 gene is associated with human T1D. We have shown that the variants of this gene that afford T1D risk in mice do so because they work slightly less than normal. Since the 'suppressor cells' require interleukin 2 to function, mice that make less interleukin 2 than normal have 'suppressor' cells that don't work very well; this is the reason why this gene is associated with T1D. This prompted us to investigate a related gene that is also associated with human T1D: 'Interleukin 2 receptor alpha'. This gene codes for a protein on the surface of the 'suppressor' cells that allows them to capture 'Interleukin 2'. We hypothesize that the variants of this gene that are associated with T1D are those that make less 'Interleukin 2 receptor alpha' protein. We have accumulated several lines of evidence suggesting that these genes control a broad repertoire of cell types of the immune system, which, in turn, regulate each other. The objective of this grant is to investigate how small variations in the function of the genes coding for 'Interleukin 2' and 'Interleukin 2 receptor alpha' in specific cell types cause immune dysregulation, leading to autoimmune disease. This work will help identify new therapeutic targets for T1D and other autoimmune diseases.