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* Experimental Diabetes Unit, San Raffaele Scientific Institute, Milan, Italy; and
Oncology Unit, Children’s Hospital of Philadelphia, Philadelphia, PA 19104
The regulatory function of invariant NKT (iNKT) cells for tolerance induction and prevention of autoimmunity is linked to a specific cytokine profile that comprises the secretion of type 2 cytokines like IL-4 and IL-10 (NKT2 cytokine profile). The mechanism responsible for iNKT cell differentiation toward a type 2 phenotype is unknown. Herein we show that costimulatory signals provided by the surface receptor signaling lymphocytic activation molecule (SLAM) on myeloid dendritic cells (mDC) to iNKT cells is crucial for NKT2 orientation. Additionally, we demonstrate that the impaired acquisition of an NKT2 cytokine phenotype in nonobese diabetic (NOD) mice that spontaneously develop autoimmune diabetes is due to defective SLAM-induced signals generated by NOD mDC. Mature mDC of C57BL/6 mice express SLAM and induce C57BL/6 or NOD iNKT cells to acquire a predominant NKT2 cytokine phenotype in response to antigenic stimulation with the iNKT cell-specific Ag, the 
-galactosylceramide. In contrast, mature NOD mDC express significantly lower levels of SLAM and are unable to promote GATA-3 (the SLAM-induced intracellular signal) up-regulation and IL-4/IL-10 production in iNKT cells from NOD or C57BL/6 mice. NOD mice carry a genetic defect of the Slamf1 gene that is associated with reduced SLAM expression on double-positive thymocytes and altered iNKT cell development in the thymus. Our data suggest that the genetic Slamf1 defect in NOD mice also affects SLAM expression on other immune cells such as the mDC, thus critically impairing the peripheral differentiation of iNKT cells toward a regulatory NKT2 type.
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 a joint grant from the Italian Telethon Foundation and the Juvenile Diabetes Research Foundation (GJT04011 to M.F.) and by National Institute of Diabetes and Digestive and Kidney Diseases–National Institutes of Health Grant RO1 DK65128 (to M.F.).
2 Current address: Sir William Dunn School of Pathology, University of Oxford, Oxford, U.K.
3 Current address: Experimental Immunology Unit, University of Basel, Basel, Switzerland.
4 Address correspondence and reprint requests to Dr. Marika Falcone, Experimental Diabetes Unit, Lotto Q, L30, San Raffaele Scientific Institute, Via Olgettina 60, 20312 Milan, Italy. E-mail address: falcone.marika{at}hsr.it
5 Abbreviations used in this paper: iNKT cell, invariant natural killer T cell; GalCer, -galactosylceramide; BM, bone marrow; DC, dendritic cells; DP, double positive; Flt3L, Fms-like tyrosine kinase-3 ligand; mDC, myeloid dendritic cells; NOD, nonobese diabetic; SAP, SLAM-associated protein; SLAM, signaling lymphocyte activation molecule.
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