Interleukin-17-producing decidual CD4+ T cells are not deleterious for human pregnancy when they also produce interleukin-4

BACKGROUND: Trophoblast expressing paternal HLA-C antigens resemble a semiallograft, and could be rejected by maternal CD4+ T lymphocytes. We examined the possible role in human pregnancy of Th17 cells, known to be involved in allograft rejection and reported for this reason to be responsible for miscarriages. We also studied Th17/Th1 and Th17/Th2 cells never investigated before. We defined for the first time the role of different Th17 subpopulations at the embryo implantation site and the role of HLA-G5, produced by the trophoblast/embryo, on Th17 cell differentiation. METHODS: Cytokine production by CD4+ purified T cell and T clones from decidua of normal pregnancy, unexplained recurrent abortion, and ectopic pregnancy at both embryo implantation site and distant from that site were analyzed for protein and mRNA production. Antigen-specific T cell lines were derived in the presence and in the absence of HLA-G5. RESULTS: We found an associated spontaneous production of IL-17A, IL-17F and IL-4 along with expression of CD161, CCR8 and CCR4 (Th2- and Th17-type markers) in fresh decidua CD4+ T cells during successful pregnancy. There was a prevalence of Th17/Th2 cells (producing IL-17A, IL-17F, IL-22 and IL-4) in the decidua of successful pregnancy, but the exclusive presence of Th17 (producing IL-17A, IL-17F, IL-22) and Th17/Th1 (producing IL-17A, IL-17F, IL-22 and IFN-γ) cells was found in the decidua of unexplained recurrent abortion. More importantly, we observed that Th17/Th2 cells were exclusively present at the embryo implantation site during tubal ectopic pregnancy, and that IL-4, GATA-3, IL-17A, ROR-C mRNA levels increased in tubal biopsies taken from embryo implantation sites, whereas Th17, Th17/Th1 and Th1 cells are exclusively present apart from implantation sites. Moreover, soluble HLA-G5 mediates the development of Th17/Th2 cells by increasing IL-4, IL-17A and IL-17F protein and mRNA production of CD4+ T helper cells. CONCLUSION: No pathogenic role of decidual Th17 cells during pregnancy was observed. Indeed, a beneficial role for these cells was observed when they also produced IL-4. HLA-G5 could be the key feature of the uterine microenvironment responsible for the development of Th17/Th2 cells, which seem to be crucial for successful embryo implantatio

SULFATO DE MAGNESIO Y SU ACCIÓN ANTI-INFLAMATORIA EN EXPLANTES DE PLACENTA

Desde hace más de 60 años, el sulfato de magnesio (MgSO4) es el fármaco de elección para el tratamiento de la preeclampsia en las salas de obstetricia. La etiología de la preeclampsia no ha sido establecida. Diferentes estudios, han demostrado que durante la preeclampsia se presenta una disfunción endotelial y un aumento de los medidores inflamatorios. El objetivo del presente trabajo fue evaluar el efecto del MgSO4 sobre la producción de citocinas en los explantes de placentas sanas del tercer trimestre en condiciones inflamatorias y de hipoxia. Los explantes fueron cultivados en presencia de MgSO4 o Lipopolisacáridos (LPS), tanto en normoxia como hipoxia. Un grupo de explantes fueron tratados con MgSO4 y transcurridas 24 horas se expusieron a LPS y viceversa. En normoxia, el MgSO4 incrementa los niveles de TNF-α e IL-1β, los mismos resultados se obtienen al incubar los explantes con MgSO4 y luego con LPS observándose además un incremento de IL-10. Al exponer los explantes a LPS y luego a MgSO4 aumentaron los niveles de IL-1β. En hipoxia, el MgSO4 promueve la liberación IL-1β. En los explantes expuestos a LPS y luego a MgSO4 aumentaron los niveles de IL-1β. En conclusión, el MgSO4 posee una acción anti-inflamatoria tanto en condiciones de normoxia como de hipoxia, al reducir los niveles de citocinas pro-inflamatorias (TNF-α e IL-1β) y estimular la secreción de citocinas anti-inflamatorias (IL-10) en presencia de LPS en los cultivos de explantes

HLA-G5 Induces IL-4 Secretion Critical for Successful Pregnancy through Differential Expression of ILT2 Receptor on Decidual CD4 +

Abstract Successful pregnancy in humans has been associated with production of IL-4 by T cells at the feto–maternal interface. Soluble HLA-G5 produced by trophoblasts potentially controls the decidual T cell cytokine profile. We studied the effect of HLA-G5 on the cytokine profile of purified human macrophages and Ag-specific T cells in vitro. We demonstrated that HLA-G5 increased production of IL-12 by purified peripheral blood macrophages. Although IL-12 production by macrophages is known to induce IFN-γ production by CD4+ T cells, HLA-G5 increased production of IL-4 but not IFN-γ by CD4+ T cells after Ag presentation by macrophages. We found that this apparent paradox was due to the differential expression of the ILT2 HLA-G5 receptor on activated T cells and macrophages. This receptor was upregulated in the former and downregulated in the latter after Ag presentation and activation of both cell types. This observation was confirmed in situ, where decidual macrophages and T cells are continuously exposed to HLA-G5 produced locally and activated by trophoblast alloantigens. Freshly isolated decidua basalis macrophages expressed lower levels of ILT2 than peripheral blood macrophages from the same pregnant women. They did not spontaneously produce IL-12, whereas freshly isolated decidual CD4+ T cells expressed high levels of activation markers (CD25, HLA-DR, and CD69) as well as ILT2 and spontaneously produced IL-4 but not IFN-γ. Therefore, HLA-G5 could be responsible, at least in part, via its interaction with ILT2, for decidual T cell IL-4 production, known to be crucial for successful pregnancy

MOESM1 of Interleukin-17-producing decidual CD4+ T cells are not deleterious for human pregnancy when they also produce interleukin-4

Additional file 1: Figure S1. IL-4, IL-17A and IL-17F production by peripheral blood CD4+T cell clones in successful pregnancy and unexplained spontaneous abortion.Levels of IL-4, IL-17A and IL-17F produced by the CD4+ T cell clones (N=40) obtained from the peripheral blood of women who underwent elective abortion and from women who underwent spontaneous abortion (N=40) were measured by multiplex bead-based assay. Data are represented as mean Âą SEM ( pg/ml) and the statistical analysis was performed with Wilcoxon test