Project 171629

Specialized cells of the immune system, T lymphocytes, have been trained to discriminate between harmless proteins of our own tissues, self-proteins, and dangerous proteins from pathogen agents. This discrimination process establishes that our own proteins pose no threat to the body; essentially we become 'tolerant' of self-proteins. One of the ways in which self-tolerance is maintained relies on the presence of a distinct population of T lymphocytes whose primary role is to prevent responses to self-tissues, the regulatory T cells. The regulatory T cells patrol the immune system and hold in check any T lymphocyte that might try to attack self-proteins (autoreactive T lymphocyte). This regulation is very important in preventing autoimmune diseases such as type 1 diabetes. In type 1 diabetes, insulin-producing cells, pancreatic islet beta cells, are killed by autoreactive T lymphocytes. It has been reported that regulatory T cells are potent at blocking diabetes development and generated with special stimulatory cells called dendritic cells. We used non-obese diabetic (NOD), a mouse model that spontaneously develops type 1 diabetes which in many respects closely resembles the human disease, and found that treatment with growth factor termed GM-CSF (Granulocytes macrophage-Colony Stimulating Factor) protects from diabetes. This protection from diabetes was associated with increased number of a population of dendritic cells that produced less inflammatory molecules and promote expansion of regulatory T cells. We also found that this population of dendritic cells was required for the protection from diabetes. The current proposal seeks to study in great detail molecular mechanisms that regulate the DCs work and what signals are needed for DCs to switch on regulatory T cells. A better understanding of DCs functions will help us design drugs that will promote regulatory activity in individuals that are predisposed to autoimmune disease, particularly type 1 diabetes.

investigating the molecular mechanisms by which dendritic cells regulate T cell tolerance in type 1 diabetes using the NOD mouse model