title: Interleukin-4 but not interleukin-10 protects against spontaneous and recurrent type 1 diabetes by activated CD1d-restricted invariant natural killer T-cells.
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 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-beta 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.
authors.affiliation: Autoimmunity/Diabetes Group, Robarts Research Institute, 1400 Western Road, London, Ontario N6G 2V4, Canada.
authors.forename: Qing-Sheng
authors.initials: QS
authors.lastname: Mi
authors.forename: Dalam
authors.initials: D
authors.lastname: Ly
authors.forename: Peter
authors.initials: P
authors.lastname: Zucker
authors.forename: Megan
authors.initials: M
authors.lastname: McGarry
authors.forename: Terry L
authors.initials: TL
authors.lastname: Delovitch
mesh_terms: D000818:Animals; D018949:Antigens, CD1 / Q000032:analysis*; D055610:Antigens, CD1d; D003520:Cyclophosphamide; D016207:Cytokines / Q000235:genetics; D003922:Diabetes Mellitus, Type 1 / Q000139:chemically induced / Q000517:prevention & control*; D005699:Galactosylceramides / Q000494:pharmacology; D015870:Gene Expression; D020869:Gene Expression Profiling; D006085:Graft Survival / Q000187:drug effects; D016753:Interleukin-10 / Q000378:metabolism*; D015847:Interleukin-4 / Q000378:metabolism*; D016381:Islets of Langerhans Transplantation; D007694:Killer Cells, Natural / Q000276:immunology*; D008213:Lymphocyte Activation; D051379:Mice; D016688:Mice, Inbred NOD; D018345:Mice, Knockout; D016513:Mice, SCID; D020411:Oligonucleotide Array Sequence Analysis; D020033:Protein Isoforms / Q000494:pharmacology; D055502:Secondary Prevention
chemical_list: D018949:Antigens, CD1; D055610:Antigens, CD1d; D016207:Cytokines; D005699:Galactosylceramides; D020033:Protein Isoforms; D016753:Interleukin-10; D015847:Interleukin-4; D003520:Cyclophosphamide