Christelle Faveeuw, Thierry Mallevaey, Emmanuel Maes, Frances M. Platt, Monique Capron, Jean Pierre Zanetta, Josette Fontaine, Maria Leite de-Moraes, François Trottein, Schistosomiase, paludisme et inflammation, Institut Pasteur de Lille, Réseau International des Instituts Pasteur (RIIP)-Réseau International des Instituts Pasteur (RIIP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Lille, Droit et Santé, Unité de Glycobiologie Structurale et Fonctionnelle UMR 8576 (UGSF), Institut National de la Recherche Agronomique (INRA)-Université de Lille-Centre National de la Recherche Scientifique (CNRS), Glycobiology Institute, University of Oxford [Oxford], Cytokines, hématopoïèse et réponse immune (CHRI), Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), 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. We also thank Agence National de la Recherche (programme Microbiologie, infections et Immunités, Grant APV05103ESA) for supporting the NKTschisto project. T.M. was the recipient of a doctoral fellowship from the Ministère de l’Education Nationale de la Recherche et Technique and from the Fondation pour la Recherche Médicale. F.T., J.P.Z., E.M., and M.L.d.M. are supported by the Centre National de la Recherche Scientifique, and C.F. by Institut National de la Santé et de la Recherche Médicale., We gratefully acknowledge Drs. T. Nakayama and M. Taniguchi (Chiba University, Chiba, Japan) and Dr. L. Van Kaer (Vanderbilt University, Nashville, TN) for the respective gift of Jα18−/− and CD1d−/− C57BL/6 mice. We also thank Drs. S. Akira (Osaka University, Osaka, Japan), R. Flavell (Yale University, New Haven, CT), and B. Ryffel (Centre National de la Recherche Scientifique GEM2358, Orleans, France) for the generous gift of TLR2−/−, TLR3−/−, TLR2−/−/TLR3−/−, and MyD88−/− C57BL/6 mice. Drs. R. Proia (National Institutes of Health, Bethesda, MD) and M. L. Albert (Institut Pasteur, Paris, France) are acknowledged for providing the hexB−/− and IL-12p40−/− mice, respectively. We also gratefully thank Dr. M. Kronenberg (La Jolla Institute for Allergy and Immunology, San Diego, CA) and Dr. P. van Endert (Institut National de la Santé et de la Recherche Médicale Unité 580, Hôpital Necker, Paris, France) for providing plasmid containing CD1d and β2-microglobulin genes and for preparing CD1d/α-GC tetramer, respectively. Kirin Brewery is greatly acknowledged for providing α-GC. V. Vasseur (Centre National de la Recherche Scientifique GEM2358), Nathalie Messiaen (Institut Pasteur de Lille, Lille, France), and H. Saklani (Institut Pasteur, Paris, France) are greatly acknowledged for their efforts in breeding the mice, and C. Vendeville for her outstanding technical assistance. We also thank Drs. R. Geyer and S. Meyer (University of Giessen, Giessen, Germany) and Drs. N. Thieblemont and A. Herbelin (Hôpital Nicker, Paris, France) for stimulating discussions, and Drs. D. Godfrey (University of Melbourne, Melbourne, Australia) and L. Gapin (University of Colorado, Denver, CO) for critical reading of this manuscript., Unité de Glycobiologie Structurale et Fonctionnelle - UMR 8576 (UGSF), Université de Lille-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Recherche Agronomique (INRA), Université de Lille-Centre National de la Recherche Scientifique (CNRS), University of Oxford, Réseau International des Instituts Pasteur ( RIIP ) -Réseau International des Instituts Pasteur ( RIIP ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Université de Lille, Droit et Santé, Unité de Glycobiologie Structurale et Fonctionnelle - UMR 8576 ( UGSF ), Institut National de la Recherche Agronomique ( INRA ) -Université de Lille-Centre National de la Recherche Scientifique ( CNRS ), Cytokines, hématopoïèse et réponse immune ( CHRI ), and Université Paris Descartes - Paris 5 ( UPD5 ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Centre National de la Recherche Scientifique ( CNRS )
Mouse CD1d-restricted NKT cells, including invariant (i)NKT cells, are innate cells activated by glycolipid Ags and play important roles in the initiation and regulation of immune responses. Through their ability to promptly produce large amounts of Th1 and/or Th2 cytokines upon TCR engagement, iNKT cells exert crucial functions in the immune/inflammatory system during bacterial, protozoan, fungal, and viral infections. However, their roles during metazoan parasite infection, which are generally associated with strong Th2 responses, still remain elusive. In this study, we show that during the course of murine schistosomiasis, iNKT cells exhibit an activated phenotype and that following schistosome egg encounter in the liver, hepatic iNKT cells produce both IFN-γ and IL-4 in vivo. We also report that schistosome egg-sensitized dendritic cells (DCs) activate, in a CD1d-dependent manner, iNKT cells to secrete IFN-γ and IL-4 in vitro. Interestingly, transfer of egg-sensitized DCs promotes a strong Th2 response in recipient wild-type mice, but not in mice that lack iNKT cells. Engagement of TLRs in DCs is not necessary for iNKT cell stimulation in response to egg-sensitized DCs, suggesting an alternative pathway of activation. Finally, we propose that self, rather than parasite-derived, CD1d-restricted ligands are implicated in iNKT cell stimulation. Taken together, our data show for the first time that helminths can activate iNKT cells to produce immunoregulatory cytokines in vivo, enabling them to influence the adaptive immune response.