In vivo strategies to determine how certain human class I MHC molecules contribute to type 1 diabetes susceptibility

Beta cells produce insulin, which controls how sugar is used in the body. Type 1 diabetes occurs when the immune system kills the beta cells and insulin can no longer be made. It is the T cells of the immune system that cause the death of the beta cells. One type of T cell that participates in this process is a CD8 T cell. These T cells bind to peptide fragments of beta cell proteins captured by major histocompatibility complex (MHC) molecules and displayed on the surface of beta cells. These peptide/MHC complexes activate the T cells and cause them to destroy the beta cells. There are two human MHC molecules that increase the risk of developing diabetes and cause it to occur earlier. These are HLA-A*24:02 and HLA-B*39:06. The proposed work will use new mouse strains that display these human MHC molecules on their beta cells to determine how they increase disease. The mice will also express human insulin, an important target of the T cells in humans and in mouse models of the disease. CD8 T cells will be isolated from the islets of these mice and will be used to identify the peptides that target beta cells for destruction. These peptides will be characterized in terms of their strength of MHC binding and the disease-promoting properties of the T cells that recognize them. This knowledge should allow reagents to be developed to monitor and control the activity of these destructive T cells in humans.