{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,2]],"date-time":"2026-08-02T23:46:39Z","timestamp":1785714399669,"version":"3.56.0"},"reference-count":90,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2023,10,30]],"date-time":"2023-10-30T00:00:00Z","timestamp":1698624000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Immunol."],"abstract":"<jats:p>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 TGF\u03b2 superfamily, was recently implicated during murine pregnancy as its conditional deletion (Nodal<jats:sup>\u0394\/\u0394<\/jats:sup>) in the female reproductive tract resulted in severe subfertility. Here, it was determined that despite normal preimplantation processes and healthy, viable embryos, Nodal<jats:sup>\u0394\/\u0394<\/jats:sup> females had a 50% implantation failure rate compared to Nodal<jats:sup>loxP\/loxP<\/jats:sup> controls. Prior to implantation, the expression of inflammatory cytokines MCP-1, G-CSF, IFN-<jats:italic>\u03b3<\/jats:italic> and IL-10 was dysregulated in the Nodal<jats:sup>\u0394\/\u0394<\/jats:sup> uterus. Further analysis of the preimplantation leukocyte populations in Nodal<jats:sup>\u0394\/\u0394<\/jats:sup> uteri showed an overabundance of infiltrating, pro-inflammatory CD11b<jats:sup>high<\/jats:sup> Ly6C<jats:sup>+<\/jats:sup> macrophages coupled with the absence of CD4<jats:sup>+<\/jats:sup> FOXP3<jats:sup>+<\/jats:sup> 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.<\/jats:p>","DOI":"10.3389\/fimmu.2023.1276979","type":"journal-article","created":{"date-parts":[[2023,10,30]],"date-time":"2023-10-30T08:47:40Z","timestamp":1698655660000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":6,"title":["Uterine Nodal expression supports maternal immunotolerance and establishment of the FOXP3+ regulatory T cell population during the preimplantation 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