Probing and modeling decidual natural killer cells in preterm birth

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Project Summary/Abstract The human placenta is a semi-allogeneic tissue whose growth and development requires tolerance by the maternal immune system. How this relationship is compromised in the setting of spontaneous preterm birth (sPTB) is currently unknown. In a normal pregnancy, placental cells come in close contact with maternal blood and uterine tissues yet are able to evade immune recognition throughout gestation. During this time, the maternal immune system maintains a balance of tolerance toward foreign fetal alloantigens while simultaneously staging a response to potential pathogens at the maternal-fetal interface. The nature of such maternal-fetal cellular interactions is poorly understood, particularly when it goes awry in the setting of spontaneous preterm birth (sPTB). The uterine lining, called decidua, is a particularly understudied microenvironment, containing many maternal immune cells, of which decidual natural killer (dNK) cells are the most abundant. It is at this interface where placental cells called extravillous trophoblast (EVT) come in close contact with maternal immune cells. Invasion of the decidua by fetal EVT is required for proper remodeling of the maternal uterine lining, including vascular remodeling which leads to establishment of maternal blood flow to the placenta. Interactions between placental EVT and decidual leukocytes, such as dNK, are known to facilitate maternal vascular remodeling by EVT and limit the extent of EVT invasion into the uterine wall. Indeed, problems in sPTB could result from inappropriate responses by dNK cells. Unfortunately, dNK function, including dNK-trophoblast crosstalk, is difficult to study in an ongoing pregnancy, due to lack of access to the decidual compartment, where these important interactions occur. Additionally, very few studies have characterized dNK at term when the pregnancy outcome is known. While animal models have offered some insights into these processes, they do not accurately model human placentation and pregnancy. This proposal aims to functionally and transcriptomically characterize dNK subpopulation(s) in term, with or without labor, and preterm placenta, then use induced pluripotent stem cells (iPSC) to model dNK, in the setting of both term and preterm birth. Our team has established optimized methods for differentiation of iPSC into both peripheral blood NK cells and EVT. We will now optimize a protocol for iPSC differentiation into decidual NK cells, comparing them directly to primary cells. Successful completion of this proposal will reveal underlying mechanisms through which abnormal dNK activation contributes to spontaneous preterm birth, and establish a renewable and manipulatable model of dNK at the human maternal-fetal interface.