Definitive class I human leukocyte antigen expression in gestational placentation: HLA-F, HLA-E, HLA-C, and HLA-G in extravillous trophoblast invasion on placentation, pregnancy, and parturition

Problem: The extravillous trophoblasts (EVT) express HLA-C and HLA-G, but HLA-E and HLA-F are the subject of conflicting reports. In this study, we define the HLA expression profile during active EVT placental implantation, pregnancy development, and parturition. Method of study: Immunohistochemistry, q-PCR, and Western blot were used to investigate HLA-C, HLA-E, and HLA-F placental expression across gestation from the early first trimester, late first trimester, second trimester (n=10 in each), preterm gestation (n=6) to elective term cesarean section and term vaginal deliveries (n=12, 38-41 weeks). EVT explants and Swan71 cells were used to assess HLA-C and HLA-F during active EVT migration. Results: HLA-G, HLA-C, and HLA-F were expressed by 1st-trimester EVT and became intracellular and weaker as gestation progressed. HLA-E was only expressed in 1st-trimester placenta. HLA-F and HLA-C mRNA and protein expression levels showed a significant increase in the fetal villous mesenchyme across gestation. HLA-C levels increased with labor. We detected a 100-kDa HLA-F band in early pregnancy suggesting dimer formation on the EVT surface. These results were confirmed in EVT outgrowths and Swan71 trophoblast which showed that HLA-F and HLA-G are increased on the cell surface of migrating EVT, while HLA-C was internalized. Conclusion: Expression of HLA-F and HLA-G on the cell surface of actively migrating EVT supports their specific role in early EVT invasion and interactions with uterine natural killer cells. HLA-C's limited expression to the proliferative EVT suggests a protective role in the earliest events of implantation but not in active EVT invasion. We also show for the first time that HLA-C may be involved in parturition.