The Non‐Expression of MHC Class II in Trophoblast Cells

As stated by Medawar in 1953,' the maternal-fetal relationship must be considered as a most dangerous parabiotic union, because there should be a potential risk for maternal rejection of the alien conceptus. Amazingly, maternal immunological rejection reactions against the fetoplacental unit are extremely rare. In fact, nature has been forced to ensure safe protection mechanisms, which most probably include the silencing of genes that encode potentially dangerous cell surface antigens. Because major histocompatibility complex (MHC) molecules can serve as strong antigens and have a central role in the development of both cellular and humoral immune responses, it can be assumed that strict regulation of their expression at the maternal-fetal interface is of importance, to ensure a successful ge~tat ion. ~ '~ Consequently, the placenta appears to be incapable of eliciting a classical T-cellmediated immunologic rejection response. In mouse, rat, and human hemichorial placentas, trophoblast expression of MHC class 11 antigens is normally completely prohibited, whereas class I gene expression is differentially regulated among trophoblast subpopu1ations. &l2 Interferon (1FN)-y is one of the major inducers of MHC class I1 expression and is normally secreted by activated T lymphocytes and natural killer cells. Most studies on the in vitro effects of IFN-y have shown that placental cells resist induction of class I1 surface expression, whereas class I expression can be induced in some placental subpopulation^. ^-' In 1991 and 1992, we were able to c o n f m the data obtained from in vitro studies by treating mice with different amounts of IFN-y in ~ i v o . * , ~ The results were very clear-cut with respect to the class I1 expression. High amounts of IFN-y induced a considerable class I1 expression in the maternally divided decidual portion of the placenta, whereas true extraembryonic cells, such as giant cells, spongiotrophoblast and labyrinthine trophoblast cells were completely negative when assayed by class I1 surface expression. In 1994, Yuan et all0 also demonstrated that the extraembryonic portion of the rat placenta lacked class I1 mRNA, even if treated with IFN-y or the demethylating drug 5-azacytidine. A similarly designed study, performed on mice of different strains at our laboratory, fully confirmed these observations. " In this context, it should be mentioned that strongly contradictory results have been published on class I1 expression in murine trophoblast cells. I personally believe this is a result of histological misinterpretations and/or induction of pathological conditions by uncontrolled environmental factors (possibly pathogens). This issue has been analyzed and discussed elsewhere. " The mechanism by which class I1 expression is silenced in trophoblast cells has, until now, been very unclear. The presence of functional IFN-y receptors on murine spongiotrophoblast cells was indicated about 10 years ago by in vitro and in vivo experiments showing that class I expression could be induced by treatment with this cyt~kine. ~'* In 1992, Peyman and co-workers'' reported that human leukocyte antigen (HLA)-DR genes are silenced in trophoblast cells of human origin and that this phenomenon could not be explained by an inability to respond to IFN-y. Furthermore, in 1994, Chen et a1.l3 provided direct evidence for the expression of IFN-y receptors in murine spongiotrophoblast cells after the midgestation stage. Functional IFN-y receptors are expressed, therefore, at certain stages of gestation, in subpopulations of placental trophoblast cells in both humans and rodents. In addition, recent results have shown that cotransfections of class I1 A a and p genes can indeed result in a functional expression of class I1 surface molecules on cells of trophoblast origin.I4 Taken together, these results indicate that the silencing of class I1 expression in trophoblast cells occurs in the signal transduction chain, somewhere in between IFN-y receptor binding and the induction of class I1 gene expression. In 1994, Stiemle et al." isolated a class I1 transactivator (CIITA) that was characterized as a transcriptional coactivator for MHC class I1 genes. They showed that CIITA is the general regulator of both constitutive and IFN-y-inducible MHC class I1 expression. Because CIITA is the gene that is actually induced by IFN-y and subsequently activates class I1 genes, it was tempting to speculate that CIITA expression might be silenced in trophoblast cells in both humans and rodents. The validity of this hypothesis in the human situation has now been experimentally tested by Jeremy Boss and co-workers.