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Diabetes 53:1303-1310, 2004
© 2004 by the American Diabetes Association, Inc.

Interleukin-4 but not Interleukin-10 Protects Against Spontaneous and Recurrent Type 1 Diabetes by Activated CD1d-Restricted Invariant Natural Killer T-Cells

Qing-Sheng Mi1, Dalam Ly1,2, Peter Zucker1, Megan McGarry1, and Terry L. Delovitch1,2

1 Autoimmunity/Diabetes Group, Robarts Research Institute, London, Ontario, Canada
2 Department of Microbiology and Immunology, University of Western Ontario, London, Ontario, Canada

In nonobese diabetic (NOD) mice, a deficiency in the number and function of invariant natural killer T-cells (iNKT cells) contributes to the onset of type 1 diabetes. The activation of CD1d-restricted iNKT cells by {alpha}-galactosylceramide ({alpha}-GalCer) corrects these deficiencies and protects against spontaneous and recurrent type 1 diabetes. Although interleukin (IL)-4 and IL-10 have been implicated in {alpha}-GalCer–induced protection from type 1 diabetes, a precise role for these cytokines in iNKT cell regulation of susceptibility to type 1 diabetes has not been identified. Here we use NOD.IL-4–/– and NOD.IL-10–/– knockout mice to further evaluate the roles of IL-4 and IL-10 in {alpha}-GalCer–induced protection from type 1 diabetes. We found that IL-4 but not IL-10 expression mediates protection against spontaneous type 1 diabetes, recurrent type 1 diabetes, and prolonged syngeneic islet graft function. Increased transforming growth factor-ß gene expression in pancreatic lymph nodes may be involved in {alpha}-GalCer–mediated protection in NOD.IL-10–/– knockout mice. Unlike the requirement of IL-7 and IL-15 to maintain iNKT cell homeostasis, IL-4 and IL-10 are not required for {alpha}-GalCer–induced iNKT cell expansion and/or survival. Our data identify an important role for IL-4 in the protection against type 1 diabetes by activated iNKT cells, and these findings have important implications for cytokine-based therapy of type 1 diabetes and islet transplantation.

Address correspondence and reprint requests to Dr. Terry L. Delovitch, Director, Autoimmunity/Diabetes Group, Robarts Research Institute, 1400 Western Rd., London, Ontario N6G 2V4, Canada. E-mail: del{at}robarts.ca


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