Project 461072

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 and resistance to T1D are both genetically determined, but the mechanisms are poorly understood. By exploring mechanisms underlying the resistance to T1D afforded by variants of different T1D-associated genes, we have discovered that these variants generally operate by regulating 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 equivalent of the 'Human Leukocyte Antigen (HLA)' gene that is associated with T1D. We have provided experimental evidence that the variants of this gene that afford T1D resistance do so because they can turn diabetes-causing white blood cells into diabetes-suppressor cells that can blunt the initiation and progression of T1D in individuals at risk. By defining and comparing the molecular structures (at the atomic level) of T1D-associated and T1D-protective HLA molecules interacting with the corresponding receptors on white blood cells, we have identified what we think are the key structural elements on anti-T1D HLA molecules that enable them to protect the host from developing T1D. The objective of this proposal is to investigate which of these specific structural elements are necessary and sufficient to turn diabetogenic white blood cells into anti-diabetogenic ones. Understanding how normal genetic variation protects us from developing autoimmune diseases like T1D will help identify new therapeutic targets for these disorders.