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* Institut National de la Santé et de la Recherche Médicale U805,
Confocal Microscopy Core Facility,
Institut National de la Santé et de la Recherche Médicale U790,
Center of Clinical Investigations CBT507,
¶ Institut Gustave Roussy, and
|| University Paris-Sud, Villejuif;
# Institut National de la Santé et de la Recherche Médicale, Laboratory of Mononuclear Phagocyte Biology, Necker Enfants Malades Institute, Paris; and
** Centre National de la Recherche Scientifique, Institut Transgénose, Orléans, France;
Section of General Pathology and Immunology, University of Brescia, Brescia, Italy; and
* Department of Immunology and Cell Biology, Research Center Borstel, Borstel, Germany
IFN-producing killer dendritic cells (IKDC) were initially described as B220+CD11c+CD3–NK1.1+ tumor-infiltrating cells that mediated part of the antitumor effects of the combination therapy with imatinib mesylate and IL-2. In this study, we show their functional dependency on IL-15 during homeostasis and inflammatory processes. Trans-presentation of IL-15 by IL-15R
allows dramatic expansion of IKDC in vitro and in vivo, licenses IKDC for TRAIL-dependent killing and endows IKDC with immunizing potential, all three biological attributes not shared by B220–NK cells. However, IL-15 down-regulates the capacity of IKDC to induce MHC class I- or II-restricted T cell activation in vitro. Trans-presentation of IL-15 by IL-15R allows IKDC to respond to TLR3 and TLR4 ligands for the production of CCL2, a chemokine that is critical for IKDC trafficking into tumor beds (as described recently). We conclude that IKDC represent a unique subset of innate effectors functionally distinguishable from conventional NK cells in their ability to promptly respond to IL-15-driven inflammatory processes.
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 European Union grants (ALLOSTEM, DC THERA), Association pour la Recherche sur le Cancer, and Ligue Nationale contre le Cancer (équipes labelisées de G. Kroemer and L.Z.). E.U. received a fellowship from the Deutsche Forschungsgemeinschaft and from the Fondation pour la Recherche Médicale, M.B. was supported by the Poste d’Accueil Institut National de la Santé et de la Recherche Médicale, and G.M. by the Association pour la Recherche sur le Cancer.
2 E.U. and M.B. contributed equally to this work.
3 Address correspondence and reprint requests to Dr. Laurence Zitvogel, Institut National de la Santé et de la Recherche Médicale U805, Center of Clinical Investigations CBT507, Institut Gustave Roussy, 39 rue Camille Desmoulins, 94805 Villejuif, France. E-mail address: zitvogel{at}igr.fr
4 Abbreviations used in this paper: IKDC, interferon-producing killer dendritic cells; BMDC, bone marrow-derived DC; IM, imatinib mesylate; rm, recombinant murine; ODN, oligodeoxynucleotide; rh, recombinant human.
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