title: X-Chromosome complement and estrogen receptor signaling independently contribute to the enhanced TLR7-mediated IFN-α production of plasmacytoid dendritic cells from women.
abstract: Human plasmacytoid dendritic cells (pDCs) play a major role in innate immunity through the production of type I IFNs after TLR engagement by pathogens. Sex-based differences in the innate function of human pDCs have been established, with pDCs from women exhibiting enhanced TLR7-mediated IFN-α production as compared with pDCs from males. In mice, we recently provided evidence for a role of estrogens as a positive regulator of pDC innate functions through cell-intrinsic estrogen receptor α signaling, but did not exclude a role for other X-linked factors, particularly in human pDCs. In this study, we investigated the respective contribution of X chromosome dosage and sex hormones using a humanized mouse model in which male or female NOD-SCID-β2m(-/-) were transplanted with human progenitor cells purified from either male or female cord blood cells. We showed that, in response to TLR7 ligands, the frequency of IFN-α- and TNF-α-producing pDCs from either sex was greater in female than in male host mice, suggesting a positive role for estrogens. Indeed, blockade of estrogen receptor signaling during pDC development in vitro inhibited TLR7-mediated IFN-α production by human pDCs, which expressed both ESR1 and ESR2 genes. Interestingly, we also found that X chromosome dosage contributed to this sex bias as female pDCs have an enhanced TLR7-mediated IFN-α response as compared with male ones, irrespective of the sex of the recipient mice. Together, these results indicate that female sex hormones, estrogens, and X chromosome complement independently contribute to the enhanced TLR7-mediated IFN-α response of pDCs in women.
authors.affiliation: INSERM, Unité Mixte de Recherche 1043, Toulouse F-31300, France; Centre National de la Recherche Scientifique, U5282, Toulouse F-31300, France; Centre de Physiopathologie de Toulouse Purpan, Université Toulouse 3, Toulouse F-31300, France;
authors.forename: Sophie
authors.initials: S
authors.lastname: Laffont
authors.affiliation: INSERM, Unité Mixte de Recherche 1043, Toulouse F-31300, France; Centre National de la Recherche Scientifique, U5282, Toulouse F-31300, France; Centre de Physiopathologie de Toulouse Purpan, Université Toulouse 3, Toulouse F-31300, France;
authors.forename: Nelly
authors.initials: N
authors.lastname: Rouquié
authors.affiliation: INSERM, Unité Mixte de Recherche 1043, Toulouse F-31300, France; Centre National de la Recherche Scientifique, U5282, Toulouse F-31300, France; Centre de Physiopathologie de Toulouse Purpan, Université Toulouse 3, Toulouse F-31300, France;
authors.forename: Pascal
authors.initials: P
authors.lastname: Azar
authors.affiliation: INSERM, Unité Mixte de Recherche 1043, Toulouse F-31300, France; Centre National de la Recherche Scientifique, U5282, Toulouse F-31300, France; Centre de Physiopathologie de Toulouse Purpan, Université Toulouse 3, Toulouse F-31300, France;
authors.forename: Cyril
authors.initials: C
authors.lastname: Seillet
authors.affiliation: Recherche et Développement Laboratoire, Etablissement Français du Sang Rhône-Alpes, La Tronche F-38701, France; Université Joseph Fourier, Grenoble F-38041, France; and Immunobiology and Immunotherapy of Cancers, INSERM U823, La Tronche F-38701, France.
authors.forename: Joël
authors.initials: J
authors.lastname: Plumas
authors.affiliation: Recherche et Développement Laboratoire, Etablissement Français du Sang Rhône-Alpes, La Tronche F-38701, France; Université Joseph Fourier, Grenoble F-38041, France; and Immunobiology and Immunotherapy of Cancers, INSERM U823, La Tronche F-38701, France.
authors.forename: Caroline
authors.initials: C
authors.lastname: Aspord
authors.affiliation: INSERM, Unité Mixte de Recherche 1043, Toulouse F-31300, France; Centre National de la Recherche Scientifique, U5282, Toulouse F-31300, France; Centre de Physiopathologie de Toulouse Purpan, Université Toulouse 3, Toulouse F-31300, France; Jean-Charles.Guery@inserm.fr.
authors.forename: Jean-Charles
authors.initials: JC
authors.lastname: Guéry
mesh_terms: D000818:Animals; D002454:Cell Differentiation; D002478:Cells, Cultured; D003713:Dendritic Cells / Q000502:physiology*; D047628:Estrogen Receptor alpha / Q000235:genetics; D047629:Estrogen Receptor beta / Q000235:genetics; D005260:Female; D018628:Gene Dosage; D050172:Genes, X-Linked / Q000235:genetics; D018380:Hematopoietic Stem Cell Transplantation; D006412:Hematopoietic Stem Cells / Q000502:physiology*; D006801:Humans; D007113:Immunity, Innate; D016898:Interferon-alpha / Q000378:metabolism; D008297:Male; D051379:Mice; D016513:Mice, SCID; D015398:Signal Transduction / Q000235:genetics / Q000276:immunology; D051199:Toll-Like Receptor 7 / Q000378:metabolism*; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism
chemical_list: D047628:Estrogen Receptor alpha; D047629:Estrogen Receptor beta; D016898:Interferon-alpha; D051199:Toll-Like Receptor 7; D014409:Tumor Necrosis Factor-alpha