Decidual-Placental Immune Landscape During Syngeneic Murine Pregnancy

Abstract

Adaptive immune system, principally governed by the T cells—dendritic cells (DCs) nexus, is an essential mediator of gestational fetal tolerance and protection against infection. However, the exact composition and dynamics of DCs and T cell subsets in gestational tissues are not well understood. These are controlled in human physiology by a complex interplay of alloantigen distribution and presentation, cellular/humoral active and passive tolerance, hormones/chemokines/angiogenic factors and their gradients, systemic and local microbial communities. Reductive discrimination of these factors in physiology and pathology of model systems and humans requires simplification of the model and increased resolution of interrogative technologies. As a baseline, we have studied the gestational tissue dynamics in the syngeneic C57BL/6 mice, as the simplest immunological environment, and focused on validating the approach to increased data density and computational analysis pipeline afforded by highly polychromatic flow cytometry and machine learning interpretation. We mapped DC and T cell subsets, and comprehensively examined their maternal (decidual)—fetal (placental) interface dynamics. Both frequency and composition of decidual DCs changed across gestation, with a dramatic increase in myeloid DCs in early pregnancy, and exclusion of plasmacytoid DCs. CD4+ T cells, in contrast, were lower at all gestational ages and an unusual CD4−CD8−TCRαβ+group was prominent at mid-pregnancy. Dimensionality reduction with machine learning-aided clustering revealed that CD4−CD8− T cells were phenotypically different from CD4+ and CD8+ T cells. Additionally, divergence between maternal decidual and fetal placental compartment was prominent, with absence of DCs from the placenta, but not decidua or embryo. These results provide a novel framework and a syngeneic baseline on which the specific role of alloantigen/tolerance, polymicrobial environment, and models of pregnancy pathology can be precisely modeled and analyzed.

Thymus-Derived Regulatory T Cells Exhibit Foxp3 Epigenetic Modification and Phenotype Attenuation after Mating in Mice

“…MFI analysis of these clusters showed several Treg phenotype markers were differentially abundant between cluster 1 and 2, not just Nrp1, again supporting the interpretation that these are distinct cell lineages. A similar dimensionality reduction with machine learning-aided clustering approach was recently shown to be informative in identifying novel leukocyte populations in the pregnant uterus (76), and it offers the potential to also identify unusual CD4 + T cell subsets in the dLN. The significance of Foxp3 + Nrp1 lo CD4 + T cells visible as a small cluster to the right of cluster 1 in the tSNE contour plots is unknown, but the proportion of these cells among CD4 + T cells did not increase in response to FIGURE 6.…”

Maternal Obesity and the Uterine Immune Cell Landscape: The Shaping Role of Inflammation

“…Timeline of human and mouse pregnancies with relative abundance of major decidual leukocytes. Important hallmarks during pregnancy are shown as well as the abundance of decidual Mφ (green), uNKs (blue), regulatory T cells (Tregs) (orange), and total CD3 + T cells (purple)[23][24][25]. Y-axis represents percent of total leukocytes in the decidua.…”

β3-Adrenoceptors as Putative Regulator of Immune Tolerance in Cancer and Pregnancy

“…In fact, this study was performed on a simplified pregnancy model, between syngeneic animals with restricted polygenic diversity. However, in C57BL/6J pregnant mice, immune tolerance is preserved and therefore this mouse strain can represent a valid model for exploratory studies ( 117 ). Rather, the demonstration that the blockade of β3-ARs induces a sensitive modulation of the cells involved in fetal immune tolerance in this “low immunologic impact” model could suggest an even more relevant impact in allogeneic pregnancies.…”