Grant: Operating Grant

Type 1 Diabetes (T1D) results from immune dysregulation (autoimmunity) leading to destruction of the insulin-producing cells of the pancreas (ß cells) by specific white blood cells (ß cell-killer lymphocytes). It has been known for quite some time that development of overt autoimmune diseases, like diabetes, is preceded by prolonged periods of inflammation of the target tissues by white blood cells. We have discovered a mechanism that accounts for that puzzling observation. Namely, we found that evolution of inflammation to overt diabetes is driven by those inflammatory white blood cells that can most easily (faster and for longer periods of time) engage target cells. Importantly, these "strong" white blood cells are rare at the outset of the disease process but are selected for within the inflammatory lesions with time (the months or years it takes for inflammation to lead to overt disease). This process of selection is akin to the "survival of the fittest", where "strong" cells multiply more easily and kill their targets better than "weak" cells. An issue that remains unresolved is the molecular basis of this phenomenon. In aims 1 and 2, we will investigate how these "strong" white blood cells choose their antigenic targets, namely what makes specific proteins in ß-cells preferable targets for these white blood cells. During the previous funding cycle, we have also discovered that the "weak" counterparts of these "strong" ß-cell killer white blood cells function as active suppressors of disease progression. In aim 3, we will investigate why and how "strong" and "weak" white blood cells turn into aggressors and suppressors, respectively. Overall, this grant proposal is an effort to dissect, in detail, the mechanisms that govern competition among "gangs" of white blood cells for occupation of the intra-islet space. The information gained through these studies will further our understanding of autoimmunity, and identify new targets for therapeutic intervention.