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.