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      miR-466a Targeting of TGF-β2 Contributes to FoxP3 + Regulatory T Cell Differentiation in a Murine Model of Allogeneic Transplantation

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          Abstract

          The promise of inducing immunological tolerance through regulatory T cell (Treg) control of effector T cell function is crucial for developing future therapeutic strategies to treat allograft rejection as well as inflammatory autoimmune diseases. In the current study, we used murine allograft rejection as a model to identify microRNA (miRNA) regulation of Treg differentiation from naïve CD4 cells. We performed miRNA expression array in CD4 + T cells in the draining lymph node (dLN) of mice which received syngeneic or allogeneic grafts to determine the molecular mechanisms that hinder the expansion of Tregs. We identified an increase in miRNA cluster 297-669 (C2MC) after allogeneic transplantation, in CD4 + T cells, such that 10 of the 27 upregulated miRNAs were all from this cluster, with one of its members, mmu-miR-466a-3p (miR-466a-3p), targeting transforming growth factor beta 2 (TGF-β2), as identified through reporter luciferase assay. Transfection of miR-466a-3p in CD4 + T cells led to a decreased inducible FoxP3 + Treg generation while inhibiting miR-466a-3p expression through locked nucleic acid resulting in increased Tregs and a reduction in effector T cells. Furthermore, in vivo inhibition of miR-466a-3p in an allogeneic skin-graft model attenuated T cell response against the graft through an increase in TGF-β2. TGF-β2 was as effective as TGF-β1 at both inducing Tregs and through adoptive transfer, mitigating host effector T cell response against the allograft. Together, the current study demonstrates for the first time a new role for miRNA-466a-3p and TGF-β2 in the regulation of Treg differentiation and thus offers novel avenues to control inflammatory disorders.

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          Most cited references37

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          Transforming growth factor-beta regulation of immune responses.

          Transforming growth factor-beta (TGF-beta) is a potent regulatory cytokine with diverse effects on hemopoietic cells. The pivotal function of TGF-beta in the immune system is to maintain tolerance via the regulation of lymphocyte proliferation, differentiation, and survival. In addition, TGF-beta controls the initiation and resolution of inflammatory responses through the regulation of chemotaxis, activation, and survival of lymphocytes, natural killer cells, dendritic cells, macrophages, mast cells, and granulocytes. The regulatory activity of TGF-beta is modulated by the cell differentiation state and by the presence of inflammatory cytokines and costimulatory molecules. Collectively, TGF-beta inhibits the development of immunopathology to self or nonharmful antigens without compromising immune responses to pathogens. This review highlights the findings that have advanced our understanding of TGF-beta in the immune system and in disease.
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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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              Micromanagement of the immune system by microRNAs.

              MicroRNAs (miRNAs) are an abundant class of evolutionarily conserved small non-coding RNAs that are thought to control gene expression by targeting mRNAs for degradation or translational repression. Emerging evidence suggests that miRNA-mediated gene regulation represents a fundamental layer of genetic programmes at the post-transcriptional level and has diverse functional roles in animals. Here, we provide an overview of the mechanisms by which miRNAs regulate gene expression, with specific focus on the role of miRNAs in regulating the development of immune cells and in modulating innate and adaptive immune responses.
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                Author and article information

                Contributors
                URI : https://frontiersin.org/people/u/499425
                URI : https://frontiersin.org/people/u/451427
                URI : https://frontiersin.org/people/u/499453
                Journal
                Front Immunol
                Front Immunol
                Front. Immunol.
                Frontiers in Immunology
                Frontiers Media S.A.
                1664-3224
                09 April 2018
                2018
                : 9
                : 688
                Affiliations
                Department of Pathology, Microbiology and Immunology, University of South Carolina School of Medicine , Columbia, SC, United States
                Author notes

                Edited by: Geraldo Aleixo Passos, Universidade de São Paulo, Brazil

                Reviewed by: Walter J. Storkus, University of Pittsburgh, United States; John Even Schjenken, University of Adelaide, Australia

                *Correspondence: Prakash S. Nagarkatti, prakash@ 123456mailbox.sc.edu

                Specialty section: This article was submitted to Alloimmunity and Transplantation, a section of the journal Frontiers in Immunology

                Article
                10.3389/fimmu.2018.00688
                5900016
                29686677
                abbe1d37-ce35-43e1-8a7c-0c71c75e0ad6
                Copyright © 2018 Becker, Nagarkatti and Nagarkatti.

                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) and the copyright owner 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
                : 20 November 2017
                : 20 March 2018
                Page count
                Figures: 7, Tables: 2, Equations: 0, References: 52, Pages: 18, Words: 10636
                Funding
                Funded by: National Institutes of Health 10.13039/100000002
                Award ID: R01ES019313, R01MH094755, R01AI123947, R01AI129788, P01AT003961, P20GM103641, and R01AT006888
                Categories
                Immunology
                Original Research

                Immunology
                allotransplantation,epigenetics,micrornas,transforming growth factor beta 2,t regulatory cells

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