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* Microbiology and Tumor Biology Center and Strategic Research Center for Studies of Integrated Recognition in the Immune System, Karolinska Institute, Stockholm, Sweden;
Centre d’Immunologie de Marseille-Luminy, Université de la Méditerranée, Case 906, Marseille, France;
Institut National de la Santé et de la Recherche Médicale, Unité 631, Marseille, France;
Centre National de la Recherche Scientifique, Unité Mixte de Recherche 6102, Marseille, France;
¶ Section of Vaccine Research, Swedish Institute for Infectious Disease Control, Solna, Sweden; and
|| Department of Molecular Microbiology and Immunology, Division of Biology and Medicine, Brown University, Providence, RI 02912
DAP12 is an ITAM-containing adaptor molecule conveying activating properties to surface receptors on many cell types. We show here that DAP12 paradoxically down-modulates plasmacytoid dendritic cell (pDC) cytokine production in vivo during murine CMV (MCMV) infection. Higher levels of IFN-
and IL-12 were detected upon MCMV infection or CpG treatment in DAP12-deficient (DAP12°) mice as compared with wild-type (WT) mice. This resulted from altered homeostasis and enhanced responsiveness of pDCs in DAP12° animals. Increased numbers of pDCs were observed in the periphery of both naive and MCMV-infected DAP12° mice. A higher proportion of pDCs was activated in infected DAP12° mice, as demonstrated by intracellular staining using an optimized protocol for simultaneous detection of IFN- and IFN-. The homeostasis of WT and DAP12° pDCs did not differ in mixed bone marrow chimeric mice. In addition, a similar efficiency of pDC differentiation was observed in vitro in Fms-like tyrosine kinase receptor 3 ligand cultures of WT and DAP12° bone marrow cells. This suggests that DAP12 signaling effects on pDC homeostasis are indirect. In contrast, in response to CpG, DAP12-mediated effects on both IL-12 and IFN- production were intrinsic to the pDCs. However, in response to MCMV, only IL-12 but not IFN- production was affected by pDC-intrinsic DAP12 signaling. Thus, DAP12 signaling in pDCs can mediate different regulatory effects on their functions, depending on the mechanisms of pDC activation. The potential implications of the regulation of pDC functions by DAP12 for promoting health over disease are discussed.
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 in part by an Actions Thématiques Initiatives sur Programmes grant from Centre National de la Recherche Scientifique (CNRS) (to M.D.), a grant from Association pour la Recherche sur le Cancer (to M.D.), and support from the Swedish Foundation for Strategic Research and the Swedish Research Council (to K.K. and H.S.). S.H.R. was supported by CNRS, Fondation pour la Recherche Médicale, the Philippe Foundation, and the city of Marseille. Centre d’Immunologie de Marseille-Luminy is supported by institutional grants from Institut National de la Santé et de la Recherche Médicale, CNRS, and Université de la Méditerranée.
2 H.S. and S.H.R. contributed equally to this work.
3 Address correspondence and reprint requests to Dr. Marc Dalod, Centre d’Immunologie de Marseille-Luminy, Parc Scientifique de Luminy, Case 906, F-13288 Marseille Cedex 09, France. E-mail address: dalod{at}ciml.univ-mrs.fr
4 Abbreviations used in this paper: pDC, plasmacytoid dendritic cell; DC, dendritic cell; cDC, conventional DC; MCMV, murine cytomegalovirus; DAP12°, DAP12-deficient; BM, bone marrow; BMC, bone marrow chimeric; FLT3-L, Fms-like tyrosine kinase receptor 3 ligand; ODN, oligodeoxynucleotide; PDCA-1, plasmacytoid DC Ag 1; WT, wild type.
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