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Prostaglandin D₂ Inhibits the Production of IFN- by Invariant NK T Cells: Consequences in the Control of B16 Melanoma¹

David Torres^*,,, Christophe Paget^*,,, Josette Fontaine^*,,, Thierry Mallevaey, Toshiyuki Matsuoka^¶, Takayuki Maruyama^||, Shuh Narumiya^¶, Monique Capron^*,,, Philippe Gosset^,,, Christelle Faveeuw^*,, and François Trottein^2,*,,

^* Institut National de la Santé et de la Recherche Médicale, Unité 547, Institut Pasteur de Lille, Institut Fédératif de Recherche 17, Université de Lille 2, and Institut National de la Santé et de la Recherche Médicale, Unité 774, Lille, France; ^¶ Department of Pharmacology, Faculty of Medicine, Kyoto University, Kyoto, Japan; and ^|| Ono Pharmaceutical Company Limited, Osaka, Japan

Invariant NK T (iNKT) cells are a subset of innate/memory lymphocytes that recognize lipid Ags presented by CD1d-expressing APCs such as dendritic cells (DCs). Upon primary stimulation through their TCR, iNKT cells promptly produce large amounts of IFN- and/or IL-4 that play critical roles in the regulation of innate and adaptive immune responses. To date, the role of environmental factors on iNKT cell functions has been poorly investigated. In this study, we addressed the question of whether PGD₂, a potent eicosanoid lipid mediator involved in immune responses and inflammation, could be important in DC/iNKT cell cross-talk. We show that PGD₂ dramatically reduced the production of IFN-, but not IL-4, by iNKT cells in response to the superagonist -galactosylceramide (-GalCer) both in vitro and in vivo. This effect is mediated by the D prostanoid receptor 1 (DP1) expressed by DCs and iNKT cells and requires protein kinase A activation. We also report that PGD₂ and BW245C (a selective DP1 agonist) reduce the protective effects of -GalCer in B16F10-induced melanoma metastasis, an effect that depends on IFN- production by iNKT cells. As a whole, these data reveal novel pathways regulating iNKT cell biologic functions and confirm the immunoregulatory roles of PGD₂ on the innate response.

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 Institut National de la Santé et de la Recherche Médicale, the Pasteur Institute of Lille, and the University of Lille 2. D.T. and C.P. are recipients of a postdoctoral or a doctoral fellowship from the Conseil Régional Nord-Pas-de-Calais/ Institut National de la Santé et de la Recherche Médicale. C.F. and P.G. are supported by Institut National de la Santé et de la Recherche Médicale, and F.T. by the Centre National de la Recherche Scientifique.

² Address correspondence and reprint requests to Dr. François Trottein, Institut National de la Santé et de la Recherche Médicale, Unité 547, Institut Pasteur de Lille, 1, Rue du Professeur Calmette, BP 245, 59019 Lille Cedex, France. E-mail address: francois.trottein{at}pasteur-lille.fr

³ Abbreviations used in this paper: iNKT, invariant NK T cell; 6-Bnz-cAMP, N⁶-benzoyladenosine-3',5'-cyclic monophosphate; 8-CPT-2'-O-Me-cAMP, (8-(4-chlorophenylthio)-2'-O-methyladenosine-3',5'-cyclic monophosphate; -GalCer, - galactosylceramide; cAMP, cyclic AMP; DC, dendritic cell; DP, D prostanoid receptor; Epac, exchange proteins directly activated by cAMP; ITAC, IFN-inducible T cell chemoattractant; MNC, mononuclear cell; PKA, protein kinase A; WT, wild type.