Introduction: Recent studies have shown that Erythroid progenitor cells exhibit a distinct immunosuppressive and immunoregulatory phenotype associated with the response to bacteria. Methods: The objective of this study was to comprehensively explore the traits of human bone marrow Erythroid cells through protein–protein interaction network analysis using cytokine secretion analysis, and single-cell immunoproteomic analysis using flow cytometry, as well as the re-analysis of publicly available human and mouse bone marrow Erythroid-cell transcriptomic data. Results: Our protein–protein interaction network analysis of human bone marrow Erythroid-cell protein-coding genes identified enrichment in the immune response to lipopolysaccharide, with Calprotectin and Cathepsin G being the main factors. We then mapped the Calprotectin to the CD45⁺ Erythroid cells of both humans and mice via the analysis of the publicly available scRNA-seq data. Additionally, we observed that human bone marrow Erythroid cells secrete cytokines and chemokines, such as IL-1b, IL-8, and IL-18, which are also mainly involved in the immune response to lipopolysaccharide. We also found that human and mouse bone marrow Erythroid-cell conditional media inhibit bacterial growth in vitro. Discussion: These findings suggest that both human and mouse bone marrow CD45⁺ Erythroid cells possess the potential to combat pathogenic microbes and thus play a role in innate antimicrobial immunity. Conclusions: CD45⁺ Erythroid cells are a potent immunoregulatory cell population in both humans and mice.

Cell migration capacity represents an essential function of the immune system. Pregnancy involves numerous morphogenetic events, angiogenesis, the establishment of intercellular connections, and complex interactions between maternal and fetal immune systems—all requiring precisely coordinated and regulated migratory processes. Chemokines serve as master regulators of cellular migration and communication during pregnancy, with functions extending far beyond classical immunological roles. Physiological chemokine levels maintain feto-maternal tolerance through precise spatiotemporal regulation, while their dysregulation leads to catastrophic pregnancy complications such as preeclampsia and preterm birth. The chemokine system exhibits remarkable complexity through functional redundancy and promiscuity of receptors and ligands; alternative splicing generating protein diversity; decoy receptors enabling the fine-tuning of chemokine concentrations; and heterocomplex formation creating novel biological functions. Chemokines show significant promise as diagnostic and prognostic biomarkers, while specific receptor–ligand pairs represent therapeutic targets for managing pathological and life-threatening conditions during pregnancy. Thus, the chemokine system constitutes both a fundamental biological mechanism supporting pregnancy and a promising translational target for addressing complex clinical challenges in obstetric complications. To fully harness the potential of this system, it is essential to understand both its evolutionarily conserved core functions and its gestational stage-specific adaptations.

Nucleated erythroid cells (NECs) are emerging as important immunoregulators at the feto–maternal interface, yet their chemokine profiles and functional dynamics across pregnancy remain poorly understood. Using a murine allogeneic pregnancy model (CBA × C57Bl/6), we isolated placental and splenic TER-119⁺ NECs at mid- (E12.5) and late (E19.5) gestation. Chemokine production (13-plex), chemokine receptor expression (qPCR), immunosuppressive molecules (PD-L1, TGF-β, and ROS), T-cell proliferation (CFSE), and immune cell migration (Transwell) were assessed. CD45⁺ placental NECs were the main producers of PD-L1, TGF-β, and ROS, with maximal expression at E19.5, suggesting their potential contribution to the immunosuppressive functions observed in the total TER-119⁺ population. Chemokine production showed a striking shift in CCL17 and CXCL9 from the spleen to the placenta as pregnancy advanced (E12.5 → E19.5). Splenic NECs displayed dominant expressions of CCR3 and CXCR4. Unexpectedly, CCL2 and CCL4 blockade enhanced immune cell migration toward placental NECs at E19.5. Placental nucleated erythroid cells potently suppressed T-cell proliferation at E12.5, and this suppressive capacity remained stable until full term. Placental NECs undergo dynamic chemokine reprogramming while maintaining stable T-cell suppression. The paradoxical enhancement of migration after CCL2/CCL4 blockade suggests a complex chemokine network warranting further investigation. These findings provide new insights into the immunobiology of pregnancy and may have implications for understanding pregnancy complications.