IL-4 triggers autoimmune diabetes by increasing self-antigen presentation within the pancreatic islets

Several findings have recently questioned the long held hypothesis that cyt okines belonging to the Th2 pathway are protective in T-cell-mediated autoi mmunity. Among them, there is our previous report that pancreatic expressio n of IL-4 activated islet antigen-specific BDC2.5 T cells and rendered them able to trigger insulin-dependent diabetes mellitus in ins-IL-4/BDC2.5 mic e (Mueller et at, Immunity, 7, 1997). Here we analyze the mechanisms underl ying IL-4-mediated activation of the self-reactive BDC2.5 T cells. IL-4 is mainly known as the Th2-driving cytokine. However, IL-4 is also critical fo r DC maturation and upregulation of antigen uptake and presentation by macr ophages. In our model, we found that pancreatic expression of IL-4 activate d self-reactive BDC2.5 T cells by increasing islet antigen presentation by macrophages and dendritic cells. IL-4 could have triggered self-antigen pre sentation within the pancreatic islets both by driving maturation of DC fro m a tolerizing to a priming state and by increasing self-antigen uptake by macrophages. (C) 2001 Academic Press.