Abstract
BackgroundRegulatory T cells (Tregs) play an important role in fine-tuning of immune responses and are pivotal for a successful pregnancy. Recently, the importance of mesenchymal stem cells in regulation of immune responses in general and Tregs in particular has been highlighted. Here, we hypothesized that menstrual stromal/stem cells (MenSCs) contribute to uterine immune system regulation through induction of functionally active Tregs.MethodsMenSCs were collected from 18 apparently healthy women and characterized. Bone marrow mesenchymal stem cells (BMSCs) served as a control. The effect of MenSCs on proliferation of anti-CD3/CD28-stimulated T CD4 + cells and generation of Tregs with or without pre-treatment with mitomycin C, IFN-γ and IL-1β was evaluated by flow cytometry. The potential role of IDO, PGE2, IL-6, IL-10, and TGF-β on proliferation of T CD4 + cells and generation of Tregs was assessed using blocking antibodies or agents. IDO activity was evaluated in MenSCs and BMSCs culture supernatants by a colorimetric assay. IL-10 and IFN-γ production in MenSCs-primed T CD4 + was measured using intracellular staining. To investigate the functional properties of Tregs induced by MenSCs, Treg cells were isolated and their functional property to inhibit proliferation of anti-CD3/CD28-stimulated PBMCs was assessed by flow cytometry.ResultsAccording to the results, proliferation of T CD4 + lymphocytes was enhanced in the presence of MenSCs, while pre-treatment of MenSCs with pro-inflammatory cytokines reversed this effect. PGE2 and IDO were the major players in MenSCs-induced T cell proliferation. Non-treated MenSCs decreased the frequency of Tregs, whereas after pre-treatment with IFN-γ and IL-1β, they induced functional Tregs with ability to inhibit the proliferation of anti-CD3/CD28-stimulated PBMCs. This effect was mediated through IL-6, IL-10, TGF-β and IDO. IFN-γ/IL-1β-treated MenSCs induced IL-10 and IFN-γ production in CD4 + T cells.ConclusionCollectively, these findings indicate that immunomodulatory impact of menstrual blood stem cells (MenSCs) on generation of Tregs and inhibition of T cells proliferation is largely dependent on pre-treatment with IFN-γ and IL-1β. This is the first report on immunomodulatory impact of MenSCs on Tregs and highlights the pivotal role of endometrial stem cells in regulation of local endometrial immune responses.
Highlights
Regulatory T cells (Tregs) play an important role in fine-tuning of immune responses and are pivotal for a successful pregnancy
Bone marrow-derived mesenchymal stem cells (BMSCs) from four healthy donors were obtained from Avicenna Research Institute (ARI) biobank, and buffy coats were collected from Iranian Blood Transfusion Organization (IBTO)
In our previous study, using protein microarray, we showed that menstrual blood stem cells (MenSCs) condition media contained considerably lower level of IGFBP1-4 (Insulin-like growth factor-binding protein) compared to Bone marrow mesen‐ chymal stem cells (BMSCs), leaving higher functional free form of insulin-like growth factors (IGFs) to exert trophic activity [44]
Summary
Regulatory T cells (Tregs) play an important role in fine-tuning of immune responses and are pivotal for a successful pregnancy. Regulatory T cells (Tregs), as one of the main regulators of the immune system, play an important role in fine-tuning of immune responses and preventing autoimmunity. The frequency of circulatory Tregs in non-pregnant fertile women reaches to the highest level between days 9 to 13 of follicular phase and reduces during the luteal phase of the menstrual cycle [3], which is believed to be essential to prepare the uterus for encountering the paternal antigens and possible implantation [4]. Tregs are quickly recruited to uterus draining lymph nodes and are activated during the first 2 days after the implantation [1]. The importance of Tregs for successful pregnancy in mice is substantiated by exploiting an adoptive transfer model. In this model, transferring Treg-depleted T cell population to nu/nu BALB/c mice led to fetus rejection in allogeneic mating, whereas transferring total T cell population resulted in successful pregnancy [1]
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