BeWo-derived extracellular vesicles downregulate IL-6Rα expression via miRNAs on CD4+ T lymphocytes

Regulatory T lymphocytes are essential for maternal immunotolerance. Their de novo differentiation in the placenta is regulated by local intercellular interactions involving primed uterine immune cells, fetal syncytiotrophoblasts, and the cytokine environment. Trophoblast-derived, HLA-G-positive extracellular vesicles (EVs) can bind to T lymphocytes, thereby influencing their differentiation and cytokine production. Thus, these EVs play a role in establishing and maintaining a tolerogenic environment. In our study, we used the BeWo choriocarcinoma cell line to model the effects of trophoblast-derived EVs. Large EVs derived from BeWo cells (BeWo-12.5K lEVs) reduce IL-6R expression on CD4+ T cells. This modifies the IL-6 pathway by downregulating the transcription factors STAT3 and NFKB1, and PIAS3, while upregulating STAT1. This may be caused by specific microRNAs (miRNAs), such as hsa-mir-92a-3p, hsa-mir-520f-3p, and hsa-mir-25-3p. These microRNAs are present in BeWo-12.5K lEVs and target the IL-6 pathway. BeWo-12.5K lEVs induce phenotypic and functional changes in T cells, enhancing the ratio of CD4+/CD25+ T cells that produce IL-10. Pregnancy-associated IL-6R downregulation has been demonstrated in clinical samples. Significantly lower levels of IL-6R were detected on circulating CD4+CD25+ T cells in healthy pregnant women than in healthy non-pregnant individuals. This finding reflects the in vivo significance of our in vitro studies. Our studies suggest that communication between maternal and fetal cells significantly influences the development and maintenance of local T cell polarity. The microRNA content of HLA-G+ 12.5K lEVs appears to be key to this process, as it alters the IL-6 pathway.