HUMAN PLACENTAL HLA-G EXPRESSION IS RESTRICTED TO DIFFERENTIATED CYTOTROPHOBLASTS

Human placental trophoblasts lie at the maternal-fetal interface, a po sition in which they could play an important role in maternal toleranc e of the fetal semi-allograft. Central to this hypothesis is their unu sual MHC class expression: they suppress class la production while exp ressing HLA-C, a class Ib molecule. We investigated human trophoblast HLA-C protein production in vivo and in vitro. We first used a synthet ic peptide corresponding to the variable sequence of the alpha 1 domai n to produce mAbs that recognized HLA-C. Ab specificity was demonstrat ed by immunoaffinity purification of a single protein with the same mo lecular mass (38 kDa) as HLA-G from choriocarcinoma cells. Use of thes e Abs to stain tissue sections of the maternal-fetal interface contain ing cytotrophoblasts in all stages of differentiation showed that HLA- G is expressed only by cytotrophoblasts that invade the uterus. Our pr evious in vitro studies showed that when early-gestation cytotrophobla st stem cells are cultured, they differentiate rapidly along the invas ive pathway, as demonstrated by their expression oi stage-specific mar kers. Here we show they also up-regulate HLA-G production. Cytotrophob lasts from term placentas, which have reduced invasive capacity in vit ro, also had decreased ability to up-regulate HLA-G protein expression . We detected high levels of HLA-G mRNA in cytotrophoblasts isolated f rom first- and second-trimester placentas, but only trace amounts in t erm cells. Taken together, these results suggest that HLA-G production is a critical component of cytotrophoblast differentiation along the invasive pathway.