Abstract
BackgroundTrophoblast 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.MethodsCytokine 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.ResultsWe 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.ConclusionNo 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.Electronic supplementary materialThe online version of this article (doi:10.1186/s12948-016-0039-y) contains supplementary material, which is available to authorized users.
Highlights
Trophoblast expressing paternal HLA-C antigens resemble a semiallograft, and could be rejected by maternal CD4+ T lymphocytes
Associated production of IL‐17 and IL‐4 and expression of Th17 and Th2‐type molecules by decidual CD3+CD4+ T cells in successful pregnancy Unstimulated decidual and peripheral blood CD4+CD3+ T cells purified from the same 9 pregnant women were cultured for 24 h and IL-4, IL-17A, IL-17F and IL-22 production was measured in the corresponding cell culture supernatants (Fig. 1a)
Using multicolor flow cytometry analysis, we found that the percentage of CD3+CD4+ cells expressing CD161 (p = 0.027) and the mean fluorescence intensity (MFI) of CD161 were increased in the decidua compared to peripheral blood of the same 8 pregnant women (Fig. 1c)
Summary
Trophoblast expressing paternal HLA-C antigens resemble a semiallograft, and could be rejected by maternal CD4+ T lymphocytes. The most effective cytokines to enhance the generation or expansion of human Th17 cells are IL-1β and IL-23 [8, 9]. Cytokines such as IL-23 and IL-21 promote the generation or proliferation of Th17 cells, whereas others such as IFN-γ, IL-4, and IL-27, seem to suppress their generation [5, 6, 8, 10, 11]. The major role of Th17 is the protection against extracellular bacteria by activating epithelial cells, macrophages, fibroblasts and endothelial cells, which produce chemokines and cytokines responsible for granulocyte recruitment, which contributes to chronic tissue inflammation. The pathogenic role of Th17 cells has been suggested in several murine models of chronic inflammatory disorders, such as experimental autoimmune encephalomyelitis (EAE) [11], collagen-induced arthritis [9], and bowel inflammatory disorders [12]
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