Decidual stromal cells support tolerance at the human foetal-maternal interface by inducing regulatory M2 macrophages and regulatory T-cells

• Published in: Journal of reproductive immunology 2021-08, Vol.146, p.103330-103330, Article 103330
• Main Authors: Lindau, R., Vondra, S., Spreckels, J., Solders, M., Svensson-Arvelund, J., Berg, G., Pollheimer, J., Kaipe, H., Jenmalm, M.C., Ernerudh, J.
• Format: Article
• Language: English
• Subjects: Abortion, Induced; Adult; Cell Survival - immunology; Cells, Cultured; Cesarean Section; Culture Media, Conditioned - metabolism; Decidua; Decidua - cytology; Decidua - immunology; Decidua - metabolism; Female; Foetal-maternal interface; Humans; Immune regulation; Immune Tolerance; Macrophage; Macrophages - immunology; Maternal-Fetal Exchange - immunology; Medicin och hälsovetenskap; Paracrine Communication - immunology; Pregnancy; Pregnancy Trimester, First - immunology; Pregnancy Trimester, Third - immunology; Primary Cell Culture; Stromal cell; Stromal Cells - immunology; Stromal Cells - metabolism; T-Lymphocytes, Regulatory - immunology; Treg cell
• ISSN: 0165-0378; 1872-7603; 1872-7603
• DOI: 10.1016/j.jri.2021.103330

[Display omitted] •Decidual stromal cells induce and promote survival of decidual-type macrophages.•Decidual stomal cells induce regulatory T-cells in a paracrine manner.•Both 1st trimester and term stromal cells possess these immune regulatory abilities.•Protein profiling supports prominent regulatory functions of decidual stromal cells.•Decidual stromal cells may initiate and support fetal-maternal immune tolerance. During pregnancy, the semi-allogeneic nature of the foetus requires maternal immune adaption and acquisition of tolerance at the foetal-maternal interface. Macrophages with regulatory properties and regulatory T (Treg) cells are central in promoting foetal tolerance and are enriched in the decidua (the uterine endometrium during pregnancy). Although tissue-resident decidual stromal cells (DSC) have been implicated in regulatory functions, it is not known if they are able to induce the regulatory phenotype of macrophages and T-cells. In this study we report that maternally derived DSC are able to induce homeostatic M2 macrophages and Treg cells. CD14+ monocytes and CD4+ T-cells from healthy non-pregnant women were cultured in the presence or absence of conditioned medium (CM) from DSC isolated from 1st trimester and term placentas. DSC-CM alone was able to promote the survival of macrophages and to induce a regulatory CD14brightCD163+CD209+CD86dim phenotype, typical for decidual macrophages and similar to that induced by M-CSF. Interestingly, DSC-CM was also able to overrule the pro-inflammatory effects of GM-CSF by upregulating CD14, CD163 and CD209. Protein-profiling showed that M-CSF was secreted by DSC, and blocking of M-CSF partially reversed the M2 phenotype and reduced viability. DSC-CM also expanded CD25brightFoxp3+ Treg cells, an expansion that was abolished by a SMAD3-inhibitor, indicating the contribution of TGF-β signaling. In conclusion, our findings collectively emphasize the role of tissue-resident stromal cells in shaping the tolerogenic environment at the foetal-maternal interface.