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, but Not β, Is Required for Optimal Dendritic Cell Differentiation and CD40-Induced Cytokine Production1
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* Institut National de la Santé et de la Recherche Médicale U563, Centre de Physiopathologie de Toulouse Purpan;
Institut National de la Santé et de la Recherche Médicale U858, Institut de Médecine Moléculaire de Rangueil;
Université Paul Sabatier;
Centre Hospitalier Universitaire, Toulouse;
¶ Centre National de la Recherche Scientifique, Unité Mixte de Recherche 6101, Faculté de Médecine, Limoges; and
|| Institut de Génétique et de Biologie Moléculaire et Cellulaire, Centre National de la Recherche Scientifique, Institut National de la Santé et de la Recherche Médicale, Université Louis Pasteur, Collège de France, Illkirch, France
Dendritic cells (DC) are critical actors in the initiation of primary immune responses and regulation of self-tolerance. The steroid sex hormone 17β-estradiol (E2) has been shown to promote the differentiation of DCs from bone marrow (BM) precursors in vitro. However, the estrogen receptor (ER) involved in this effect has not yet been characterized. Using recently generated ER
- or ERβ-deficient mice, we investigated the role of ER isotypes in DC differentiation and acquisition of effector functions. We report that estrogen-dependent activation of ER, but not ERβ, is required for normal DC development from BM precursors cultured with GM-CSF. We show that reduced numbers of DCs were generated in the absence of ER activation and provide evidence for a cell-autonomous function of ER signaling in DC differentiation. ER-deficient DCs were phenotypically and functionally distinct from wild-type DCs generated in the presence of estrogens. In response to microbial components, ER-deficient DCs failed to up-regulate MHC class II and CD86 molecules, which could account for their reduced capacity to prime naive CD4+ T lymphocytes. Although they retained the ability to express CD40 and to produce proinflammatory cytokines (e.g., IL-12, IL-6) upon TLR engagement, ER-deficient DCs were defective in their ability to secrete such cytokines in response to CD40–CD40L interactions. Taken together, these results provide the first genetic evidence that ER is the main receptor regulating estrogen-dependent DC differentiation in vitro and acquisition of their effector functions.
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 grants from Agence Nationale de la Recherche (ANR-PHYSIO-06-010), Ligue Régionale contre le Cancer Région Midi-Pyrénées, Association Française contre les Myopathies, and Association pour la Recherche sur la Sclérose en Plaques.
2 V.D.-E., S.L., and C.S. contributed equally to this work.
3 Address correspondence and reprint requests to Dr. Jean-Charles Guéry, Institut National de la Santé et de la Recherche Médicale U563, Centre Hospitalier Universitaire Purpan, Place du Dr Baylac, 31024 Toulouse Cedex 3, France. E-mail address: Jean-Charles.Guery{at}toulouse.inserm.fr
4 Abbreviations used in this paper: DC, dendritic cell; BM, bone marrow; BMDC, BM-derived dendritic cell; CM, conventional medium containing phenol red and regular FCS; E2, 17β-estradiol; ER, estrogen receptor; MHC-II, MHC class II; ODN, oligodeoxynucleotide; SFM, steroid-free medium; WT, wild type.
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