Th17 cells promote pancreatic inflammation but only induce diabetes efficiently in lymphopenic hosts after conversion into Th1 cells

Abstract

IDDM is characterized by leukocyte invasion to the pancreatic tissues followed by immune destruction of the islets. Despite the important function of Th17 cells in other autoimmune disease models, their function in IDDM is relatively unclear. In this study, we found association of elevated Th17 cytokine expression with diabetes in NOD mice. To understand the function of Th17 cells in IDDM, we differentiated islet-reactive BDC2.5 TcR transgenic CD4(+) cells in vitro into Th17 cells and transferred them into NOD.scid and neonate NOD mice. NOD.scid recipient mice developed rapid onset of diabetes with extensive insulitic lesions, whereas in newborn NOD mice, despite extensive insulitis, most recipient mice did not develop diabetes. Surprisingly, BDC2.5(+) cells recovered from diabetic NOD.scid mice, in comparison with those from neonate NOD mice, showed predominant IFN-gamma over IL-17 expression, indicating conversion of donor cells into Th1 cells. Moreover, diabetes progression in NOD.scid recipients was dependent on IFN-gamma while anti-IL-17 treatment reduced insulitic inflammation. These results indicate that islet-reactive Th17 cells promote pancreatic inflammation, but only induce IDDM upon conversion into IFN-gamma producers.