Estrogen Receptor α, but Not β, Is Required for Optimal Dendritic Cell Differentiation and CD40-Induced Cytokine Production

• DOI: 10.4049/jimmunol.180.6.3661
• Publication Date: 2014-04-18T23:47:10Z
• Authors: Victorine Douin-E...; Sophie Laffont; Cyril Seillet; Laurent Delpy; Andrée Krust; Pierre Chambon; Pierre Gourdy; Jean-François Arnal; Jean-Charles Guéry
• Keywords: MESH: Signal Transduction; MESH: Cell Differentiation; Male; MESH: Mice, Transgenic; MESH: Mice, Inbred BALB C; Mice, Transgenic; MESH: Stem Cells; Dendritic cells; MESH: Mice, Knockout; MESH: Antigens, CD40; Mice; 03 medical and health sciences; 0302 clinical medicine; Estrogen Receptors; MESH: Mice, Inbred C57BL; Animals; Estrogen Receptor beta; MESH: Animals; CD40 Antigens; MESH: Mice; MESH: Estrogen Receptor alpha; Cells, Cultured; Mice, Knockout; MESH: Cytokines; MESH: Estrogen Receptor beta; Mice, Inbred BALB C; 0303 health sciences; MESH: Dendritic Cells; Estradiol; Stem Cells; Estrogen Receptor alpha; Granulocyte-Macrophage Colony-Stimulating Factor; Cell Differentiation; Dendritic Cells; MESH: Granulocyte-Macrophage Colony-Stimulating Factor; MESH: Male; 3. Good health; Mice, Inbred C57BL; [SDV.IMM]Life Sciences [q-bio]/Immunology; Cytokines; Female; MESH: Estradiol; MESH: Female; Knockout mice; MESH: Cells, Cultured; Signal Transduction

Abstract 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 ERα- 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 ERα, 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 ERα activation and provide evidence for a cell-autonomous function of ERα signaling in DC differentiation. ERα-deficient DCs were phenotypically and functionally distinct from wild-type DCs generated in the presence of estrogens. In response to microbial components, ERα-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, ERα-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 ERα is the main receptor regulating estrogen-dependent DC differentiation in vitro and acquisition of their effector functions.