The importance of Tregs for successful pregnancy in mice is substantiated by exploiting an adoptive transfer model. In the early stages of mouse pregnancy, the origin of accumulated Tregs in uterine draining lymph is thymus that will substitute for periphery in later pregnancy stages. In pregnant mice, Tregs are quickly recruited to uterus draining lymph nodes and are activated during the first 2 days after the implantation. Frequency of murine endometrial Tregs peaks in the estrus phase and then declines during metestrus and remains low until the next estrus. Treg frequency is then diminished throughout the weeks prior to the childbirth and a clear decrease is seen after the delivery, even though it is still slightly higher than non-pregnant women. In very early stages of human pregnancy, systemic and local frequency of Tregs in decidua, lymph nodes and spleen is increased and reaches its peak on second semester of gestation. Along with that, it is known that same alteration in Treg population can be observed in murine estrus cycle.
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, which is believed to be essential to prepare the uterus for encountering the paternal antigens and possible implantation. The presence of Tregs in the uterus and their positive impact in successful pregnancy have been fully understood.
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. 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. ConclusionĬollectively, 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. IFN-γ/IL-1β-treated MenSCs induced IL-10 and IFN-γ production in CD4 + T cells. This effect was mediated through IL-6, IL-10, TGF-β and IDO. 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. PGE2 and IDO were the major players in MenSCs-induced T cell proliferation. ResultsĪccording 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. 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. IL-10 and IFN-γ production in MenSCs-primed T CD4 + was measured using intracellular staining. IDO activity was evaluated in MenSCs and BMSCs culture supernatants by a colorimetric assay. 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. 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. Bone marrow mesenchymal stem cells (BMSCs) served as a control. MenSCs were collected from 18 apparently healthy women and characterized. Here, we hypothesized that menstrual stromal/stem cells (MenSCs) contribute to uterine immune system regulation through induction of functionally active Tregs. Recently, the importance of mesenchymal stem cells in regulation of immune responses in general and Tregs in particular has been highlighted. Regulatory T cells (Tregs) play an important role in fine-tuning of immune responses and are pivotal for a successful pregnancy.
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