Uterine Nodal expression supports maternal immunotolerance and establishment of the FOXP3 regulatory T cell population during the preimplantation period.

Pregnancy success is dependent on the establishment of maternal tolerance during the preimplantation period. The immunosuppressive function of regulatory T cells is critical to limit inflammation arising from implantation of the semi-allogeneic blastocyst. Insufficient maternal immune adaptations to pregnancy have been frequently associated with cases of female infertility and recurrent implantation failure. The role of Nodal, a secreted morphogen of the TGFβ superfamily, was recently implicated during murine pregnancy as its conditional deletion (Nodal) in the female reproductive tract resulted in severe subfertility. Here, it was determined that despite normal preimplantation processes and healthy, viable embryos, Nodal females had a 50% implantation failure rate compared to Nodal controls. Prior to implantation, the expression of inflammatory cytokines MCP-1, G-CSF, IFN- and IL-10 was dysregulated in the Nodal uterus. Further analysis of the preimplantation leukocyte populations in Nodal uteri showed an overabundance of infiltrating, pro-inflammatory CD11b Ly6C macrophages coupled with the absence of CD4 FOXP3 regulatory T cells. Therefore, it is proposed that uterine Nodal expression during the preimplantation period has a novel role in the establishment of maternal immunotolerance, and its dysregulation should be considered as a potential contributor to cases of female infertility and recurrent implantation failure.