MHC Molecules of the Preimplantation Embryo and Trophoblast

The mechanisms of protection of the allogeneic fetus from the maternal immune response during pregnancy remain mysterious more than fifty years after the paradox of maternal tolerance was first raised by Peter Medawar. Preimplantation embryos express paternal antigens early in development. After implantation, placental tissue is derived from both maternal tissue and paternal-antigen expressing fetal tissue that is in intimate association with and bathed in maternal blood. There appears to be a key role for an unusual subset of major histocompatibility complex (MHC) Class I proteins of both maternal and paternal origin in the mediation of tolerance at the maternal/fetal interface and in the control of preimplantation embryonic growth rate. This subset of MHC products is composed of two nonclassical MHC Class Ib proteins, HLA-E and HLA-G in combination with a classical MHC Class la protein, HLA-C. This chapter reviews the history of the discovery of the major histocompatibilty complex Class I genes and the elucidation of the biological role of the proteins encoded by these genes in the immune response and in reproduction. MHC genes have also been implicated in reproductive choice and nurturing behaviors. We hypothesize that the vertebrate immune system derived from ancestral recognition systems driven by reproductive requirements, and was later coopted for immune recognition under additional evolutionary pressures. The complex interactions of MHC Class I proteins with components of both the innate and the adaptive immune systems in the context of the preimplantation embryo and the trophoblast of early pregnancy are described in detail, as are the difficulties inherent in studying these systems. Finally, potential future directions of research and the need for new model systems to study both preimplantation embryos and the maternal/fetal placental interface are discussed.