Antigen Presentation at the Maternal–Fetal Interface Historically, it was proposed that one method by which the implanting trophoblastic allograft potentially could avoid immune detection by the maternal host would be by making itself antigenically invisible. It could downregulate its expression of the MHC-encoded transplantation antigens (some of which would be of paternal origin) and thereby avoid recognition as non-self. Although current knowledge of immunology renders this theory obsolete, the implanting fetus does utilize this strategy to some extent (160). It is certainly true that placental trophoblast cells do not express MHC class II molecules (161,162).
Unlike nearly every other cell in the human body, trophoblast cells do not express the classical MHC class I transplantation antigens HLA-A and -B. Rather, a subpopulation of placental cells, specifically the extravillous cytotrophoblast cells, express the classical MHC class I HLA-C products, and the nonclassical HLA-E and -G products (120,163–167). These extravillous cytotrophoblast cells are of particular interest because they are characterized by remarkable invasive potential (168,169). These cells move from the tips of the anchoring villae of the human placenta, invading deeply into the maternal decidua, and can replace cells within the walls of decidual arterial vessels (168–170). Although the invasive characteristics of extravillous cytotrophoblast may reﬂect non-MHC–related mechanisms, including well-described integrin switching, the intimate contact of these fetal-derived cells with maternal immune effector cells certainly exposes the fetus to recognition as nonself (171).
It is not known why all placental cells downregulate expression of HLA-A and -B, whereas invasive extravillous cytotrophoblast express HLA-C, -E, and -G. This area of investigation is ripe with hypotheses and study. Because NK cells of the innate immune system recognize and kill cells that express no MHC, the complete downregulation of MHC should cause trophoblast cells to act as targets for those NK cells that are pervasive at sites of implantation (134,160). In addition to possible protection from direct NK cell–mediated killing, the expression of HLA-C, -E, and -G by trophoblast cells may serve a variety of alternate purposes. NK cell receptor-mediated interactions with extravillous cytotrophoblast MHC products modulate cytokine expression profiles at the maternal–fetal interface (131,132). MHC expression aids in decidual and vascular invasion by the trophoblast, an activity essential for proper placental development (172). Whereas definitive correlations between placental MHC class I expression patterns and recurrent pregnancy loss have not been reported, trophoblast expression of HLA-G was linked to other disorders of placental invasion, such as preeclampsia (172,173). Genetic mutations at the HLA-G locus have also been linked to recurrent pregnancy loss in some, but not all studies (174–177). Finally, soluble or secreted trophoblast MHC products may aid in the development of maternal immune tolerance toward the placenta (178). Soluble HLA-G was shown to suppress T lymphocyte and NK cell function and to induce the expansion of Treg cells in humans (179).