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^Δ/Δ) in the female reproductive tract resulted in severe subfertility. Here, it was determined that despite normal preimplantation processes and healthy, viable embryos, Nodal^Δ/Δ females had a 50% implantation failure rate compared to Nodal^loxP/loxP controls. Prior to implantation, the expression of inflammatory cytokines MCP-1, G-CSF, IFN-γ and IL-10 was dysregulated in the Nodal^Δ/Δ uterus. Further analysis of the preimplantation leukocyte populations in Nodal^Δ/Δ uteri showed an overabundance of infiltrating, pro-inflammatory CD11b^high 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.