Dendritic Cells and Macrophages Are the First and Major Producers of TNF-α in Pancreatic Islets in the Nonobese Diabetic Mouse

Abstract The nonobese diabetic (NOD) mouse spontaneously develops autoimmune insulin-dependent diabetes mellitus (IDDM) and serves as an animal model for human type I diabetes. TNF-α is known to be produced by islet-infiltrating mononuclear cells during insulitis and subsequent β cell destruction and has been implicated in the pathogenesis of IDDM. Previously, T cells have been suggested as the main source of TNF-α in the islet infiltrate. However, on immunohistochemical analysis of TNF-α expression in islets, we are able to show that the staining pattern of TNF-α resembles that of dendritic cells (DC) and macrophages (Mφ) rather than T cells and that TNF-α is expressed in islets at the very early stages of insulitis when no T cells are detected. On double staining for TNF-α and cell surface markers, we can demonstrate that TNF-α staining clearly correlates with DC and Mφ, whereas there is a poor correlation with T cells. This feature was observed at both early and late stages of insulitis. TNF-α expression was also seen in NOD-SCID islets, in addition to a peri-islet infiltration consisting of DC and Mφ, indicating that T cells are not required for the early DC and Mφ infiltration and TNF-α expression in islets. In conclusion, our results show that DC and Mφ are the major, early source of TNF-α in the NOD islet infiltrate and that TNF-α can be expressed independently of T cells, indicating that the early DC and Mφ infiltration and expression of TNF-α are crucial in initiation of diabetes.