Preeclampsia is a pregnancy-specific disorder that gives rise to severe complications for both the mother and the fetus. Its onset may be linked to a breakdown of the immune tolerance that the maternal organism normally develops toward the embryo at the maternal–fetal interface. Previous work had reported reduced expression of the HLA-F molecule at this interface in affected patients, without elucidating the mechanism by which this molecule contributes to immune tolerance. It is this question that the present study seeks to clarify.
To map the immune disturbances at the maternal–fetal interface, the authors performed single-cell RNA sequencing on placental decidua. In total, 101,250 cells were classified into 22 distinct clusters. This approach was complemented by functional experiments on two human cell lines: Jar cells, a trophoblast model, and NK-92MI cells, a lymphocyte model, in order to define the role played by HLA-F in each of these cell types.
The analysis revealed, in preeclamptic placental decidua, a particular population of extravillous trophoblasts characterized by the co-expression of IGFBP1 and SPP1, associated with several previously undescribed immune dysfunctions: a decrease in the ribosomal functions of NK cell populations and abnormal expression of antigen-presentation molecules in the majority of cell clusters. Certain genes specific to the intermediate stages of differentiation of myeloid cells or extravillous trophoblasts were found to be involved in the pathophysiology of the disease; in particular, enhanced intercellular communication was observed between IGFBP1+SPP1+ (EVT2) or SPP1+M1 cells and their target populations in patients, compared with controls. With regard to HLA-F, multiplex immunofluorescence staining confirmed its lower expression in preeclamptic samples. In Jar cells, HLA-F overexpression promoted cell proliferation, invasion, and migration, whereas its underexpression produced the opposite effect. In NK-92MI cells, HLA-F overexpression increased the secretion of immunoregulatory cytokines such as CSF1 and CCL22 and promoted the conversion of NKG2C+ adaptive NK cells.
By describing the landscape of immune disturbances at the maternal–fetal interface, this work sheds new light on the cellular heterogeneity, immune dysfunctions, and the role of HLA-F in preeclampsia. The authors consider that these findings offer new perspectives for the study of disease mechanisms and may point to a potential therapeutic target.