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

Abstract

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 implantation.

The role and mechanism of vitamin D‐mediated regulation of Treg/Th17 balance in recurrent pregnancy loss

“…5 Treg cells have a highly suppressive function that enables the control of some inflammatory diseases, making them a potential and attractive candidate for human immunotherapy. 16 Growing evidence indicates that Treg and Th17 cells have functions in the establishment and maintenance of pregnancy. 16 Growing evidence indicates that Treg and Th17 cells have functions in the establishment and maintenance of pregnancy.…”

The modulatory role of cytokines IL‐4 and IL‐17 in the functional activity of phagocytes in diabetic pregnant women

“…The cytokine IL‐17A, in turn, is closely associated with a number of inflammatory conditions and complications, which may culminate in persistent inflammatory processes that can develop to insulin resistance and diabetes . A recent study on pregnant women showed that cultured decidual CD4+ T cells secreted more IL‐4 and IL‐17 than peripheral blood cells and were characterized by a Th2/TH17 cytokine profile . During pregnancy, women with chronic and gestational diabetes have increased levels of plasma IL‐17 compared with healthy individuals .…”

THE ROLE OF THE DIFFERENT SUBPOPULATIONS OF CD4⁺Т LYMPHOCYTES DURING PREGNANCY

“…On the other hand, Th17 through active TNFα secretion promote Treg activation [19]. In the implantation zone and decidua, increased concentration of unique population of Th17/Th2-lymphocytes (normally quite small in human) compared to peripheral blood was noted [68]. These cells facilitate successful pregnancy development, while their lack results in implantation disorder [68].…”

“…In women with recurrent spontaneous abortions, an increased Th1 and Th17 lymphocyte levels and reduced Th2 content in peripheral blood were found [62,68]. Probably, imbalance between Treg and Th17 can contribute to pregnancy loss or its severe gestational disorders.…”

“…RANTES, secreted by trophoblast and T cells, can be one of the mechanisms of tolerance formation, being, during the first trimester, a positive regulator of implantation through induction of pro-inflammatory cytokine secretion in moderate amounts, and, on the other hand, causing effector T cell apoptosis and promoting Treg differentiation [33,140]. Recent researches indicate that sHLA-G5, secreted by trophoblast, promotes formation of Th17/Th2 cell pool in the decidua and reduces the amount of Th17/ Th1 or Th17/Th0 clones [68]. Trophoblast cells are the source of hemoxygenase-1 (HO-1), which significantly contributes to physiological pregnancy establishment and immune tolerance formation.…”