Human pDCs display sex-specific differences in type I interferon subtypes and interferon α/β receptor expression

The outcomes of many diseases differ between women and men, with women experiencing a higher incidence and more severe pathogenesis of autoimmune and some infectious diseases. It has been suggested that this is partially due to activation of plasmacytoid dendritic cells (pDCs), the main producers of interferon (IFN)-alpha, in response to toll-like receptor (TLR) 7 stimulation. We investigated the induction of type I IFN (IFN-I) subtypes upon TLR7 stimulation on isolated pDCs. Our data revealed a sex-specific differential expression of IFN-Is, with pDCs from females showing a significantly higher mRNA expression of all 13 IFN-alpha subtypes. In addition, pDCs from females had higher levels of IFN-beta mRNA after stimulation, indicating that sex differences in IFN- I production by pDCs were mediated by a signaling event upstream of the first loop of IFN- I mRNA transcription. Furthermore, the surface expression levels of the common IFN- alpha/beta receptor subunit 2 were significantly higher on pDCs from females in comparison to males. These data indicate that higher IFN-alpha production is already established at the mRNA level and propose a contribution of higher IFN- alpha/beta receptor 2 expression on pDCs to the immunological differences in IFN- I production observed between females and males.