Sperm modulate uterine immune parameters relevant to embryo implantation and reproductive success in mice

Seminal fluid factors modulate the female immune response at conception to facilitate embryo implantation and reproductive success. Whether sperm affect this response has not been clear. We evaluated global gene expression by microarray in the mouse uterus after mating with intact or vasectomized males. Intact males induced greater changes in gene transcription, prominently affecting pro-inflammatory cytokine and immune regulatory genes, with TLR4 signaling identified as a top-ranked upstream driver. Recruitment of neutrophils and expansion of peripheral regulatory T cells were elevated by seminal fluid of intact males. In vitro, epididymal sperm induced IL6, CXCL2, and CSF3 in uterine epithelial cells of wild-type, but not Tlr4 null females. Collectively these experiments show that sperm assist in promoting female immune tolerance by eliciting uterine cytokine expression through TLR4-dependent signaling. The findings indicate a biological role for sperm beyond oocyte fertilization, in modulating immune mechanisms involved in female control of reproductive investment. Components of the seminal fluid are required for specific gene expression and immune changes in the uterus following mating, but the role that sperm play in this process has remained unclear. Here, John Schjenken et al. compare female mice mated to intact and vasectomized males and show that sperm are required for the full post-mating response, indicating a broader role for sperm in reproduction beyond fertilization.

Automated summary

The seminal fluid factors modulate the female immune response to facilitate embryo implantation and reproductive success, with intact males inducing greater changes in gene transcription and affecting immune regulatory genes. Sperm assist in promoting female immune tolerance by eliciting uterine cytokine expression through TLR4-dependent signaling, indicating a biological role beyond oocyte fertilization.