Human placental exosomes induce maternal systemic immune tolerance by reprogramming circulating monocytes

Abstract

Background The maternal immune system needs to tolerate the semi-allogeneic fetus in pregnancy. The adaptation occurs locally at the maternal–fetal interface as well as systemically through the maternal circulation. Failure to tolerate the paternal antigens may result in pregnancy complications, such as pregnancy loss and pre-eclampsia. However, the mechanism that regulates maternal immune tolerance, especially at the systemic level, is still an enigma. Here we report that the first-trimester placenta-derived exosomes (pEXOs) contribute to maternal immune tolerance by reprogramming the circulating monocytes. Results pEXOs predominantly target monocytes and pEXO-educated monocytes exhibit an immunosuppressive phenotype as demonstrated by reduced expression of marker genes for monocyte activation, T-cell activation and antigen-process/presentation at the transcriptomic level. They also have a greater propensity towards M2 polarization when compared to the monocytes without pEXO treatment. The inclusion of pEXOs in a monocyte-T-cell coculture model significantly reduces proliferation of the T helper cells and cytotoxic T cells and elevates the expansion of regulatory T cells. By integrating the microRNAome of pEXO and the transcriptomes of pEXO-educated monocytes as well as various immune cell functional assays, we demonstrate that the pEXO-derived microRNA miR-29a-3p promotes the expression of programmed cell death ligand-1, a well-known surface receptor that suppresses the adaptive immune system, by down-regulation of phosphatase and tensin homolog in monocytes. Conclusions This is the first report to show how human pEXO directly regulates monocyte functions and its molecular mechanism during early pregnancy. The results uncover the importance of pEXO in regulating the maternal systemic immune response during early pregnancy by reprogramming circulating monocytes. The study provides the basis for understanding the regulation of maternal immune tolerance to the fetal allograft. Graphical Abstract

The dark side of foetal bovine serum in extracellular vesicle studies

“…The authors demonstrated that EVs from FBS could be internalized by airway epithelial cancer cells and promote their migratory ability in a dose‐dependent manner, supporting the idea that FBS‐EVs can affect cell behaviour (Shelke et al., 2014). Because EVs isolated from the human placenta are involved in foetal protection by exerting immunosuppressing functions (Bai et al., 2022; Stenqvist et al., 2013), FBS‐derived EVs might possess similar activities and mediate cross‐species protection of cell cultures. In a work by Beninson and Fleshner, the immunomodulatory properties of FBS‐EVs on cell cultures were evaluated (Beninson & Fleshner, 2015).…”

Trophoblast-Derived Extracellular Vesicles Promote Preeclampsia by Regulating Macrophage Polarization

“…There are differences between THP-1 cell lines and the peripheral monocyte-derived macrophages. Moreover, considering that peripheral monocytes in pregnant women have been educated by T-EVs and that functions or phenotypes of monocyte-macrophages varied with gestation, 7,19 we used monocytes from nonpregnant women rather than from pregnant women for the in vitro experiments. Though early onset preeclampsia is associated with severe maternal and perinatal complications, 34 abnormal M1/M2 macrophage polarizations were observed in patients with PE regardless of their subtype (Figure S1).…”

“…17 For instance, T-EVs isolated from first trimester normal placenta reportedly inhibited NK cells and T cells cytotoxicity 18 and reprogrammed circulating monocytes to induce maternal systemic immune tolerance. 19 However, T-EVs isolated from preeclamptic placentas or hypoxic trophoblast cell lines significantly enhance the production of proinflammatory cytokines such as IL-6 and IL-1β in peripheral blood mononuclear cells. 20,21 Accumulating evidence indicates that the quantity, composition, and function of the T-EVs isolated from pregnant women with PE (PE-EVs) differ from those isolated from healthy pregnant controls (NP-EVs).…”

Human amniotic fluid derived extracellular vesicles attenuate T cell immune response

“…Therefore, it is not surprising that EVs derived from perinatal tissue or AF would promote immunosuppression under certain environmental conditions. A previous study by another group has demonstrated placenta-derived exosomes suppress T cell proliferation and reduce expression of genes associated with T cell proliferation and activation in monocytes ( 44 ). Similarly, our data here demonstrates AF-EVs are internalized by T effector cells and can modulate immunological responses by inhibiting T cell activation and proliferation and reducing anti-inflammatory cytokine release.…”