CyTOF and single-cell RNA-seq of preeclamptic placenta identified a PE-specific immune network regulated by CD206-CD163- pro-inflammatory macrophages: they induce memory-like Th17 cells via IGF1-IGF1R (contributing to PE development and recurrence) while suppressing granulocytic myeloid-derived suppressor cells (gMDSCs). The induction arm has a defined mechanism; the suppression arm has none, and the antigen specificity of the recurrence-associated Th17 cells is untested. The open problem is to causally identify the molecular mechanism by which pro-inflammatory macrophages suppress gMDSCs at the maternal-fetal interface, to determine whether the memory-like Th17 cells that accompany PE recurrence are fetal-antigen-specific, and to validate this network in human preeclamptic placenta.

Background

Preeclampsia (PE) is a pregnancy-specific hypertensive disorder (new-onset hypertension after 20 weeks of gestation, usually with proteinuria) affecting roughly 2-8% of pregnancies; delivery remains its only cure, and its cause is debated. The fetus is a semi-allogeneic graft, so the maternal immune system must tolerize fetal antigens at the maternal-fetal interface (decidua/placenta); breakdown of this tolerance is one leading pathogenesis model. Myeloid-derived suppressor cells (MDSCs) are immature myeloid cells with strong T-cell-suppressive activity; the granulocytic subset (gMDSCs, e.g. CD11b+CD15hiHLA-DRlow in human, Ly6g+S100a8+S100a9+ in mouse) accumulates during normal pregnancy to help maintain maternal-fetal tolerance and is reduced in preeclampsia and miscarriage (Wang et al. 2018; Köstlin-Gille et al. 2019). Th17 cells are IL-17-producing pro-inflammatory CD4+ T cells that oppose regulatory T cells (Tregs); the Th17/Treg balance tilts toward Th17 in PE, and insulin-like growth factor 1 (IGF1) signaling through its receptor IGF1R promotes Th17 over Treg differentiation in autoimmunity (DiToro et al. 2020). Fei et al. (2025, eLife 13:RP100002; bioRxiv preprint 10.1101/2024.06.05.597577) combined cytometry by time of flight (CyTOF, single-cell mass cytometry of ~40 metal-tagged antibodies) and single-cell RNA sequencing (scRNA-seq) on term placentas from normal, PE, gestational-diabetes-mellitus (GDM), and GDM+PE pregnancies. PE alone showed expanded memory-like Th17 cells (CD45RA-CCR7+IL-17A+CD4+), memory-like CD8+ T cells, and CD206-CD163- pro-inflammatory macrophages (pro-inflam Macs, in mouse F4/80+CD206- with a Folr2+Ccl7+Ccl8+C1q+ phenotype), with reduced anti-inflammatory macrophages and gMDSCs. Adoptive transfer experiments — injecting sorted immune populations from PE-model mice (RUPP, reduced uterine perfusion pressure, the standard placental-ischemia PE mouse model) into normal pregnant mice — showed that pro-inflam Macs causally induce memory-like Th17 cells via macrophage IGF1 engaging IGF1R on CD4+ T cells (verified with the IGF1R inhibitor BMS-754807), induce PE-like symptoms, and suppress gMDSCs at the maternal-fetal interface; transferred CD4+CD44+ memory T cells from PE mice reproduced PE-like symptoms in a first pregnancy and memory-like Th17 cells accompanied PE recurrence in a second pregnancy. Ligand-receptor communication analysis with CellPhoneDB (a curated database/tool that scores cell-cell ligand-receptor interactions from single-cell data) nominated many macrophage-centered pairs, of which only IGF1-IGF1R was pursued. The source leaves the role of the memory-like Th17 cells in PE recurrence unconfirmed and the gMDSC-suppression arm without a mechanistic account, and its human evidence remains correlational, limited by uncontrolled BMI/gestational-age confounders and a small GDM&PE cohort.

Problem Statement

Within the preeclampsia-specific placental immune network established by Fei et al. (eLife 2025;13:RP100002) — in which CD206-CD163- pro-inflammatory macrophages (mouse Folr2+Ccl7+Ccl8+C1q+ F4/80+CD206-) simultaneously induce memory-like Th17 cells through IGF1-IGF1R and suppress Ly6g+S100a8+S100a9+Retnlg+Wfdc21+ granulocytic myeloid-derived suppressor cells at the maternal-fetal interface — the following mechanistic questions are open and jointly complete the causal account of how this network drives preeclampsia development and recurrence: (1) By what molecular mechanism do pro-inflammatory macrophages suppress gMDSCs — i.e., which step is targeted (gMDSC differentiation from granulocyte precursors, proliferation, survival, or recruitment to the decidua) and which macrophage-derived mediator or signaling pathway carries the effect? (2) Are the memory-like IL-17a+Rora+Il1r1+TNF+Cxcr6+S100a4+CD44+ Th17 cells that accompany preeclampsia recurrence in successive pregnancies fetal-antigen-specific, or are they bystander innate-like cells (this question concerns antigen specificity, not whether these cells causally contribute to recurrence)? (3) Does the macrophage-Th17-gMDSC network operate in human preeclamptic placenta beyond the correlational frequencies so far reported?

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