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      The Effect of TGF-β on Treg Cells in Adverse Pregnancy Outcome upon Toxoplasma gondii Infection

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          Abstract

          Toxoplasma gondii ( T. gondii) is a ubiquitous intracellular protozoan parasite that causes adverse pregnancy outcomes. Its infection downregulates the Treg cell population and TGF-β level, which may contribute to adverse pregnancy outcomes. TGF-β plays a critical role in Treg cell development, but whether TGF-β treatment can affect the number and function of Treg cells and hence alleviate adverse pregnancy outcomes caused by T. gondii infection remains elusive. In this study, T. gondii-infected pregnant mice were treated with TGF-β or TGF-β-neutralizing antibody. The pregnancy outcomes were observed on gestational day 14. The numbers of Treg cells and pSmad3, programmed death 1 (PD-1), and Cytotoxic T lymphocyte-associated antigen-4 (CTLA-4) expression of Treg cells were analyzed by flow cytometry. Histological changes were assessed using HE staining, while IL-10 and TNF-α levels were measured using ELISA. The results indicated that TGF-β treatment improved the T. gondii-induced adverse pregnancy outcomes, with alleviation of hemorrhage, restoration of uterine spiral arteries of the placenta, and increased Treg cell numbers; meanwhile, TGF-β neutralization resulted in more serious adverse pregnancy outcomes, with serious hemorrhage, more dilated uterine spiral arteries, and decreased Treg cell numbers. pSmad3 expression in CD4 + cells and CTLA-4 and PD-1 levels on Treg cells were upregulated by TGF-β treatment, but downregulated by TGF-β neutralization. The ratio of IL-10/TNF-α also increased after TGF-β treatment, but decreased after TGF-β neutralization. Our data indicate that TGF-β treatment could improve adverse pregnancy outcomes caused by T. gondii infection by upregulating Treg cell differentiation and function via the TGF-β/Smad3 signaling pathway, but not the proliferation of Treg cells.

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          Most cited references18

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          Transcriptional control by the TGF-beta/Smad signaling system.

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            A critical function for TGF-beta signaling in the development of natural CD4+CD25+Foxp3+ regulatory T cells.

            The molecular mechanisms directing the development of 'natural' CD4+CD25+Foxp3+ regulatory T cells (T(reg) cells) in the thymus are not thoroughly understood. We show here that conditional deletion of transforming growth factor-beta receptor I (TbetaRI) in T cells blocked the appearance of CD4+CD25+Foxp3+ thymocytes at postnatal days 3-5. Paradoxically, however, beginning 1 week after birth, the same TbetaRI-mutant mice showed accelerated expansion of thymic CD4+CD25+Foxp3+ populations. This rapid recovery of Foxp3+ thymocytes was attributable mainly to overproduction of and heightened responsiveness to interleukin 2, as genetic ablation of interleukin 2 in TbetaRI-mutant mice resulted in a complete absence of CD4+CD25+Foxp3+ cells from the thymus and periphery. Thus, transforming growth factor-beta signaling is critical to the thymic development of natural CD4+CD25+Foxp3+ T(reg) cells.
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              CD4+CD25+ TR Cells Suppress Innate Immune Pathology Through Cytokine-dependent Mechanisms

              CD4+CD25+ regulatory T (TR) cells can inhibit a variety of autoimmune and inflammatory diseases, but the precise mechanisms by which they suppress immune responses in vivo remain unresolved. Here, we have used Helicobacter hepaticus infection of T cell–reconstituted recombination-activating gene (RAG)−/− mice as a model to study the ability of CD4+CD25+ TR cells to inhibit bacterially triggered intestinal inflammation. H. hepaticus infection elicited both T cell-mediated and T cell–independent intestinal inflammation, both of which were inhibited by adoptively transferred CD4+CD25+ TR cells. T cell–independent pathology was accompanied by activation of the innate immune system that was also inhibited by CD4+CD25+ TR cells. Suppression of innate immune pathology was dependent on T cell–derived interleukin 10 and also on the production of transforming growth factor β. Thus, CD4+CD25+ TR cells do not only suppress adaptive T cell responses, but are also able to control pathology mediated by innate immune mechanisms.
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                Author and article information

                Contributors
                Journal
                Front Microbiol
                Front Microbiol
                Front. Microbiol.
                Frontiers in Microbiology
                Frontiers Media S.A.
                1664-302X
                26 May 2017
                2017
                : 8
                : 901
                Affiliations
                [1] 1Department of Radiology, Affiliated Hospital of Binzhou Medical University Binzhou, China
                [2] 2Department of Immunology, Binzhou Medical University Yantai, China
                [3] 3Medicine and Pharmacy Research Center, Binzhou Medical University Yantai, China
                Author notes

                Edited by: José Roberto Mineo, Federal University of Uberlândia, Brazil

                Reviewed by: Manuel Antonio Franco, Pontifical Xavierian University, Colombia; Emma Harriet Wilson, University of California, Riverside, United States

                *Correspondence: Xuemei Hu, xue-mei-hu@ 123456163.com

                These authors have contributed equally to this work.

                This article was submitted to Microbial Immunology, a section of the journal Frontiers in Microbiology

                Article
                10.3389/fmicb.2017.00901
                5445113
                28603517
                37991980-5809-4c43-a357-32dd1d101dcb
                Copyright © 2017 Zhao, Zhang, Liu, Jiang, Ren and Hu.

                This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) or licensor are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.

                History
                : 30 January 2017
                : 03 May 2017
                Page count
                Figures: 7, Tables: 1, Equations: 0, References: 25, Pages: 10, Words: 0
                Funding
                Funded by: National Natural Science Foundation of China 10.13039/501100001809
                Funded by: Natural Science Foundation of Shandong Province 10.13039/501100007129
                Categories
                Microbiology
                Original Research

                Microbiology & Virology
                tgf-β,psmad3,ctla-4,pd-1,treg cells,toxoplasma gondii,pregnancy outcome
                Microbiology & Virology
                tgf-β, psmad3, ctla-4, pd-1, treg cells, toxoplasma gondii, pregnancy outcome

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