Focus on beta cells instead of immune system could be key to
Type 1 diabetes is a disorder of immune tolerance that leads to the death of insulin-producing islet cells. Authors hypothesize that inflammatory signaling within cells promotes the progression of autoimmunity within the islet microenvironment. To test this hypothesis, we deleted the proinflammatory gene encoding 12/15-lipoxygenase (Alox15) in cells of non-obese diabetic mice at a pre-diabetic time point when islet inflammation is a feature. Deletion of Alox15 leads to the preservation of cell mass, reduces populations of infiltrating T cells, and protects against spontaneous autoimmune diabetes in both sexes. Mice lacking Alox15 in cells exhibit an increase in a population of cells expressing the gene encoding the protein programmed death-ligand 1 (PD-L1), which engages receptors on immune cells to suppress autoimmunity. Delivery of a monoclonal antibody against PD-L1 recovers the diabetes phenotype in knockout animals. The results support the contention that inflammatory signaling in cells promotes autoimmunity during type 1 diabetes progression.