Chemokine expression and function at the maternal-fetal interface

A long-standing unanswered biological question is how the placental-fetal unit avoids rejection by the maternal immune system. The unusual anatomy of the maternal fetal interface suggests that the mechanisms must include a regulatory dialog between the mother and fetus that subverts the standard methods of maternal self-identification and immune surveillance. Several unique immunological aspects of pregnancy have been identified; one of the most striking is the unorthodox maternal leukocyte population that homes to the pregnant uterus-decidual granulated leukocytes. Dominated by specialized CD56bright NK cells, these leukocytes are the maternal immune ambassadors that accompany the engrafted fetus through gestation. Presumably they are selected for their ability to tolerate paternal allo-antigens, yet respond to pathogens.; This thesis focuses on the influence of chemokines, molecules that control the migration and activation of leukocytes, on the decidual leukocyte population and immune responses in the placental bed. Through a combination of molecular techniques we showed that placental cells (cytotrophoblasts) produced and secreted the chemokine MIP-1α that induced a calcium flux in cells with compatible receptors. Additionally, MIP-1α was a major contributor to the chemotactic activity in cytotrophoblast conditioned medium. Neutralization of MIP-1α in the medium abrogated nearly half of the monocyte and CD56 bright NK cell migration towards cytotrophoblast conditioned medium in in vitro chemotaxis assays. The results of this study suggest the specific conclusion that cytotrophoblasts can attract monocytes and CD56bright NK cells by producing MIP-1α, and the more general hypothesis that these cells may organize and act on leukocytes at the maternal-fetal interface.; The analysis of MIP-1α expression and function at the maternal-fetal interface suggested that this molecule belonged to a network of chemokines and their receptors expressed in the pregnant uterus. Accordingly, additional experiments were initiated to identify other components of this circuitry. The results of in situ hybridization and RNase protection studies showed abundant and specific expression of chemokines and their receptors in both the placental and uterine compartments. Furthermore, the reciprocal expression of ligand-receptor pairs by decidual leukocytes and uterine tissues suggested that the expression patterns observed had functional consequences. Other localization patterns suggested that chemokines expressed at the maternal-fetal interface had novel non-immune functions, likely related to vasculogenesis/angiogenesis and autocrine regulation of cytotrophoblast differentiation. Together, the results presented suggest that chemokines are an integral component of the unusual cell-cell interactions that lead to normal placentation and immune tolerance of the hemi-allogeneic fetus.; The provocative results described here suggest numerous models of chemokine action at the maternal-fetal interface, and provide a solid informational foundation for future research that addresses specific functional questions. These include investigations into mechanisms of decidual leukocyte and Hofbauer cell recruitment, chemokine regulation of vasculogenesis/angiogenesis in both maternal and fetal compartments, and chemokine participation in placental development, particularly with regard to cytotrophoblast differentiation. Importantly, the resulting paradigms will give new insights into both normal placentation, and pregnancy complications related to placental abnormalities, such as preterm labor and preeclampsia. The results of these future studies will advance our knowledge of specific processes in human reproduction, and will provide a novel contribution to our understanding of chemokine biology.