Immunological determinants of implantation success

The capacity of the immune system to maintain the integrity of the individual requires recognition and control of entities identified as genetically distinct, or 'non-self'. In mammalian reproduction, the embryo and subsequent fetus and placenta are all recognized as non-self by the maternal immune system, and are vulnerable to immunological attack. An active system to prevent rejection must exist from when conceptus and maternal tissues first come into contact at implantation. Crucial mediators of immune protection are inducible regulatory T cells (Treg cells). Unless sufficient Treg cells are present in the endometrium, successful implantation and progression to pregnancy cannot ensue. This key role of Treg cells confers to the female immune system substantial capability to influence reproductive events, particularly around the time of conception and embryo implantation. While on the one hand this risks susceptibility to immune-based reproductive disorders, the potential evolutionary trade-off is the benefit of quality control to avoid poor reproductive outcomes. Here we summarize current knowledge of the factors required to establish a robust Treg cell response and an immune environment conducive to successful implantation and pregnancy. These factors include (a) appropriate cytokine balance; (b) correct phenotype of endometrial leukocytes to enable Treg cell activation; (c) sufficient estrogen and progesterone to stabilize and strengthen Treg cell phenotype, and (d) appropriate priming of Treg cell populations by male partner seminal fluid. Compromises in the quality of this immune adaptation at conception can influence the early embryo and either prevent implantation or impair placental morphogenesis. Failure to successfully establish Treg cell-mediated immune tolerance can result in poor fertility or impart long-term adverse consequences for the fetus and offspring.