The goal of this research is to further our understanding of the establishment and maintenance of pregnancy. We focus on understanding the actions of signals originating in trophoblast cells of the developing chorioallantoic placenta and targeted toward Natural Killer cells located within the uteroplacental compartment. Trophoblast cells are situated at the interface between maternal and extraembryonic structures and elaborate a family of proteins related to prolactin (PRL). One member of the PRL family, PRL-like protein-A (PLP-A), is synthesized by trophoblast cells and directly binds and modulates the activity of Natural Killer cells positioned in the uterus. Natural Killer cells are a part of the immune surveillance, are cytoloytically active toward various cell populations, and express an assortment of bioeffector molecules. During gestation, Natural Killer cells exhibit temporal- and spatial-specific patterns of appearance within the uteroplacental compartment proximal to the developing chorioallantoic placenta. Phenotypically, the spectrum of uterine Natural Killer cells activities undergoes a gestational- dependent transformation. By midpregnancy, uterine Natural Killer cells show minimal cytolytic activities and express a unique array of secretory products. These adjustments in Natural Killer cell function facilitate the establishment and maintenance of pregnancy. We hypothesize that the trophoblast cell-specific product, PLP-A, directs gestational-dependent changes in the behavior of uterine Natural Killer cells and in doing so facilitates the establishment and maintenance of pregnancy. In this research project, we propose to evaluate the actions of PLP- A on Natural Killer cell activities and to examine the physiological consequences of creating mice with a null mutation of the PLP-A gene. The planned research utilizes cellular and molecular and in vitro and in vivo strategies. Data derived from the proposed experimentation will improve our understanding of the nature of trophoblast-Natural Killer cell signaling and the role of uterine Natural Killer cells in the establishment and maintenance of the gestational state. These findings will provide considerable insight into the etiology of developmental disorders associated with pregnancy failure and will also have significant implications on our understanding of the control of Natural Killer cell functions in aberrant processes such as immune disease and cancer.
