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J. Exp. Med.,
Volume 189, Number 7, April 5, 1999 1053-1062
By
From the Center for Immunology and Department of Pathology, Washington University School of
Medicine, St. Louis, Missouri 63110
The islet-infiltrating and disease-causing leukocytes that are a hallmark of insulin-dependent diabetes mellitus produce and respond to a set of cytokine molecules. Of these, interleukin 1
,
tumor necrosis factor (TNF)-
, and interferon (IFN)-
are perhaps the most important. However, as pleiotropic molecules, they can impact the path leading to cell apoptosis and diabetes at multiple points. To understand how these cytokines influence both the formative and effector phases of insulitis, it is critical to determine their effects on the assorted cell types comprising the lesion: the effector T cells, antigen-presenting cells, vascular endothelium, and target
islet tissue. Here, we report using nonobese diabetic chimeric mice harboring islets deficient in
specific cytokine receptors or cytokine-induced effector molecules to assess how these compartmentalized loss-of-function mutations alter the events leading to diabetes. We found that
islets deficient in Fas, IFN- receptor, or inducible nitric oxide synthase had normal diabetes
development; however, the specific lack of TNF- receptor 1 (p55) afforded islets a profound
protection from disease by altering the ability of islet-reactive, CD4+ T cells to establish insulitis and subsequently destroy islet cells. These results argue that islet cells play a TNF--dependent role in their own demise.
receptor;
T cells;
insulitis
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