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Ligand-Dependent Induction of Noninflammatory Dendritic Cells by Anergic Invariant NKT Cells Minimizes Autoimmune Inflammation¹

Jianxiong Wang^*, Suzanne Cho^*, Aito Ueno^*, Lu Cheng^*, Bo-You Xu, Melanie D. Desrosiers, Yan Shi and Yang Yang^2,*

^* Julia McFarlane Diabetes Research Centre, Department of Biochemistry and Molecular Biology, Department of Microbiology and Infectious Diseases, and Department of Pathology, Faculty of Medicine, The University of Calgary, Canada

Stimulated by an agonistic ligand, -galactosylceramide (GalCer), invariant NKT (iNKT) cells are capable of both eliciting antitumor responses and suppressing autoimmunity, while they become anergic after an initial phase of activation. It is unknown how iNKT cells act as either activators or regulators in different settings of cellular immunity. We examined effects of GalCer administration on autoimmune inflammation and characterized phenotypes and functional status of iNKT cells and dendritic cells in GalCer-treated NOD mice. Although iNKT cells became and remained anergic after the initial exposure to their ligand, anergic iNKT cells induce noninflammatory DCs in response to GalCer restimulation, whereas activated iNKT cells induce immunogenic maturation of DCs in a small time window after the priming. Induction of noninflammatory DCs results in the activation and expansion of islet-specific T cells with diminished proinflammatory cytokine production. The noninflammatory DCs function at inflammation sites in an Ag-specific fashion, and the persistence of noninflammatory DCs critically inhibits autoimmune pathogenesis in NOD mice. Anergic differentiation is a regulatory event that enables iNKT cells to transform from promoters to suppressors, down-regulating the ongoing inflammatory responses, similar to other regulatory T cells, through a ligand-dependent mechanism.

The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ This work was supported by the Juvenile Diabetes Research Foundation International, Canadian Diabetes Association, and the Julia McFarlane Diabetes Research Centre (to Y.Y.).

² Address correspondence and reprint requests to Dr. Yang Yang, University of Calgary, Julia McFarlane Diabetes Research Center, 3330 Hospital Drive N.W., Calgary, Alberta T2N 4N1, Canada. E-mail address: yyang{at}ucalgary.ca

³ Abbreviations used in this paper: iNKT, invariant NKT; GalCer, -galactosylceramide; DC, dendritic cell; ILN, inguinal lymph nodes; MLN, mesenteric lymph node; PLN, pancreatic lymph node; T1D, type I diabetes.