X-Chromosome complement and estrogen receptor signaling independently contribute to the enhanced TLR7-mediated IFN-α production of plasmacytoid dendritic cells from women

J Immunol. 2014 Dec 1;193(11):5444-52. doi: 10.4049/jimmunol.1303400. Epub 2014 Oct 22.


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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Cell Differentiation
  • Cells, Cultured
  • Dendritic Cells / physiology*
  • Estrogen Receptor alpha* / genetics
  • Estrogen Receptor beta* / genetics
  • Female
  • Gene Dosage
  • Genes, X-Linked* / genetics
  • Hematopoietic Stem Cell Transplantation
  • Hematopoietic Stem Cells / physiology*
  • Humans
  • Immunity, Innate
  • Interferon-alpha / metabolism
  • Male
  • Mice
  • Mice, SCID
  • Signal Transduction / genetics
  • Signal Transduction / immunology
  • Toll-Like Receptor 7 / metabolism*
  • Tumor Necrosis Factor-alpha / metabolism


  • Estrogen Receptor alpha
  • Estrogen Receptor beta
  • Interferon-alpha
  • Toll-Like Receptor 7
  • Tumor Necrosis Factor-alpha