bims-reprim 2021-12-12 papers

Issue of 2021–12–12
three papers selected by
Iva Filipovic, Karolinska Institutet

J Leukoc Biol. 2021 Dec 10.

Specific innate immune cells uptake fetal antigen and display homeostatic phenotypes in the maternal circulation.

Marcia Arenas-Hernandez, Roberto Romero, Meyer Gershater, Li Tao, Yi Xu, Valeria Garcia-Flores, Errile Pusod, Derek Miller, Jose Galaz, Kenichiro Motomura, George Schwenkel, Robert Para, Nardhy Gomez-Lopez.

Pregnancy represents a period when the mother undergoes significant immunological changes to promote tolerance of the fetal semi-allograft. Such tolerance results from the exposure of the maternal immune system to fetal antigens (Ags), a process that has been widely investigated at the maternal-fetal interface and in the adjacent draining lymph nodes. However, the peripheral mechanisms of maternal-fetal crosstalk are poorly understood. Herein, we hypothesized that specific innate immune cells interact with fetal Ags in the maternal circulation. To test this hypothesis, a mouse model was utilized in which transgenic male mice expressing the chicken ovalbumin (OVA) Ag under the beta-actin promoter were allogeneically mated with wild-type females to allow for tracking of the fetal Ag. Fetal Ag-carrying Ly6G+ and F4/80+ cells were identified in the maternal circulation, where they were more abundant in the second half of pregnancy. Such innate immune cells displayed unique phenotypes: while Ly6G+ cells expressed high levels of MHC-II and CD80 together with low levels of pro-inflammatory cytokines, F4/80+ cells up-regulated the expression of CD86 as well as the anti-inflammatory cytokines IL-10 and TGF-β. In vitro studies using allogeneic GFP+ placental particles revealed that maternal peripheral Ly6G+ and F4/80+ cells phagocytose fetal Ags in mid and late murine pregnancy. Importantly, cytotrophoblast-derived particles were also engulfed in vitro by CD15+ and CD14+ cells from women in the second and third trimester, providing translational evidence that this process also occurs in humans. Collectively, this study demonstrates novel interactions between specific maternal circulating innate immune cells and fetal Ags, thereby shedding light on the systemic mechanisms of maternal-fetal crosstalk.

Keywords: OVA; human; innate immune cells; maternal-fetal tolerance; mice; peripheral blood; pregnancy

DOI: https://doi.org/10.1002/JLB.5HI0321-179RR

Front Immunol. 2021 ;12 765730

The New Old CD8+ T Cells in the Immune Paradox of Pregnancy.

Lilja Hardardottir, Maria Victoria Bazzano, Laura Glau, Luca Gattinoni, Angela Köninger, Eva Tolosa, Maria Emilia Solano.

CD8+ T cells are the most frequent T cell population in the immune cell compartment at the feto-maternal interface. Due to their cytotoxic potential, the presence of CD8+ T cells in the immune privileged pregnant uterus has raised considerable interest. Here, we review our current understanding of CD8+ T cell biology in the uterus of pregnant women and discuss this knowledge in relation to a recently published immune cell Atlas of human decidua. We describe how the expansion of CD8+ T cells with an effector memory phenotype often presenting markers of exhaustion is critical for a successful pregnancy, and host defense towards pathogens. Moreover, we review new evidence on the presence of long-lasting immunological memory to former pregnancies and discuss its impact on prospective pregnancy outcomes. The formation of fetal-specific memory CD8+ T cell subests in the uterus, in particular of tissue resident, and stem cell memory cells requires further investigation, but promises interesting results to come. Advancing the knowledge of CD8+ T cell biology in the pregnant uterus will be pivotal for understanding not only tissue-specific immune tolerance but also the etiology of complications during pregnancy, thus enabling preventive or therapeutic interventions in the future.

Keywords: Immune regulation; decidual CD8+T cells; exhaustion; fetal tolerance; feto-maternal interface; immune tolerace; pregnancy

DOI: https://doi.org/10.3389/fimmu.2021.765730

Proc Natl Acad Sci U S A. 2021 Dec 14. pii: e2111267118. [Epub ahead of print]118(50):

Intersection of regulatory pathways controlling hemostasis and hemochorial placentation.

Masanaga Muto, Damayanti Chakraborty, Kaela M Varberg, Ayelen Moreno-Irusta, Khursheed Iqbal, Regan L Scott, Ross P McNally, Ruhul H Choudhury, John D Aplin, Hiroaki Okae, Takahiro Arima, Shoma Matsumoto, Masatsugu Ema, Alan E Mast, Elin Grundberg, Michael J Soares.

Hemochorial placentation is characterized by the development of trophoblast cells specialized to interact with the uterine vascular bed. We utilized trophoblast stem (TS) cell and mutant rat models to investigate regulatory mechanisms controlling trophoblast cell development. TS cell differentiation was characterized by acquisition of transcript signatures indicative of an endothelial cell-like phenotype, which was highlighted by the expression of anticoagulation factors including tissue factor pathway inhibitor (TFPI). TFPI localized to invasive endovascular trophoblast cells of the rat placentation site. Disruption of TFPI in rat TS cells interfered with development of the endothelial cell-like endovascular trophoblast cell phenotype. Similarly, TFPI was expressed in human invasive/extravillous trophoblast (EVT) cells situated within first-trimester human placental tissues and following differentiation of human TS cells. TFPI was required for human TS cell differentiation to EVT cells. We next investigated the physiological relevance of TFPI at the placentation site. Genome-edited global TFPI loss-of-function rat models revealed critical roles for TFPI in embryonic development, resulting in homogeneous midgestation lethality prohibiting analysis of the role of TFPI as a regulator of the late-gestation wave of intrauterine trophoblast cell invasion. In vivo trophoblast-specific TFPI knockdown was compatible with pregnancy but had profound effects at the uterine-placental interface, including restriction of the depth of intrauterine trophoblast cell invasion while leading to the accumulation of natural killer cells and increased fibrin deposition. Collectively, the experimentation implicates TFPI as a conserved regulator of invasive/EVT cell development, uterine spiral artery remodeling, and hemostasis at the maternal-fetal interface.

Keywords: hemostasis; placenta; trophoblast cell; uterine spiral artery

DOI: https://doi.org/10.1073/pnas.2111267118