Immune responses at the Maternal-Fetal Interface
The maternal-fetal interface is the interface between the uterine mucosa and the extraembryonic tissues of the developing conceptus. Trophoblasts constitute the primary cell type of these extraembryonic tissues, which on one side of the conceptus form the placenta and on the other side of the conceptus contribute to the chorioamniotic membrane. The placenta functions as the primary nutrient and gas exchange organ of the fetus by diverting maternal blood flow from the uterus. Once inside the placenta, maternal blood exchanges nutrients, gases, and metabolic waste products with fetal blood coursing through a physically separate vasculature that connects to the fetus via the umbilical cord.
A successful pregnancy involves complex interactions between fetal trophoblasts, endothelial cells and maternal decidual immune cells, creating an immunologically unique site that allows the tolerance to the allogenic fetus but still maintains host defense against possible pathogens. Immune cells contribute in modulating the uterine environment to sustain a successful pregnancy. The majority of immune cells at this site are NK, they play a primary role in promoting vascular remodeling necessary for maximizing maternal blood flow through the placenta. Macrophages are the second most abundant immune cells at the maternal-fetal interface (∼20% of total leukocytes), their prominent role as pathogen sensor and immune effector cells suggest a central role in the inflammatory response to decidual or placental infection. Interestingly, Placental macrophages can be divided in fetal derived Hofbauer cells, and decidual macrophages of the maternal decidua derived from hematopoietic pluripotent stem cells. However, sub-populations and functions for these cells remain ill-defined and therefore represents an open area of research with major implications for human health.
T cells represent 10–20% of all leukocytes in the first-trimester human decidua, with ∼30–45% being CD4+ T cells and 45–75% CD8+ T cells. About 5% of the CD4+ T cell population are regulatory T cells (Treg) with immunosuppressive properties, it is thought that Treg cells enforce maternal-fetal tolerance and that a better understanding of their function will lead to new strategies for improving pregnancy outcomes. Indeed, Tregs are enriched in the bone marrow (BM) where they contribute to the maintenance of the BM as an immune privileged site, necessary for HSC survival. Previous works, using intravital imaging, could show that BM Treg cells displaye a distinct behavior characterized by sustained co-localization with CD11c-YFP+ cells and that preservation of Treg cells during systemic T. gondii infection prevented plasma cell loss, while Treg cell depletion in uninfected mice reduced PC populations. These studies highlight the role for Treg cells in the maintenance of an immune privileged niche. Interestingly, Treg cell numbers collapsed during acute toxoplasmosis, but the consequences of this phenomena for the infection of the placenta and the transmission to the fetus are not known. There is a major knowledge gap in our understanding in the cell-cell interaction of Tregs and macrophages at the Maternal-Fetal interface and how this impacts the creation of the unique immune environment in the placenta.
Aim 1. Do Treg cells interact with macrophages or Hofbauer cells at the maternal-fetal interface? Understanding how Treg cells operate under homeostatic and inflammatory conditions is critical to the development of strategies that target these populations to promote or antagonize immune responses. An appreciation of how Treg cells behave and what cell populations they interact with, and what factors promote these interactions will provide essential insight for understanding how they control the immunosuppressive environment at the maternal-fetal interface. In turn, these data become essential to generate accurate models to identify key cellular interactions that can be targeted therapeutically
Aim 2. What are the consequences of the loss of IL27 or the IL-27 receptor during homeostasis and infection during pregnancy? Cytokines play a crucial role at the fetal-maternal interface and are essential in regulating implantation and parturition and maternal tolerance to the fetus. Certain placental cytokine profiles have been shown to reflect poor pregnancy outcomes during. IL-27 is a heterodimeric cytokine and is expressed in the placenta at very high levels. However, the role of IL-27 and its receptor at the maternal-fetal interface is ill defined.