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

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 Mi 1 , Dalam Ly 1 2 , Peter Zucker 1 , Megan McGarry 1 and Terry L. Delovitch 1 2 1 Autoimmunity/Diabetes Group, Robarts Research Institute, London, Ontario, Canada 2 Department of Microbiology and Immunology, University of Western Ontario, London, Ontario, Canada 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 Abstract 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 α-galactosylceramide (α-GalCer) corrects these deficiencies and protects against spontaneous and recurrent type 1 diabetes. Although interleukin (IL)-4 and IL-10 have been implicated in α-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 α-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-β gene expression in pancreatic lymph nodes may be involved in α-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 α-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. agr;-GalCer, α-galactosylceramide BGL, blood glucose level CFA, Complete Freund’s Adjuvant CY, cyclophosphamide DC, dendritic cell IFN, interferon IL, interleukin iNKT cell, invariant natural killer T-cell PLN, pancreatic lymph node TCR, T-cell receptor TGF, transforming growth factor TNF, tumor necrosis factor Footnotes Q.-S.M. and D.L. contributed equally to this work. Q.-S.