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      Role of Blimp-1 in programing Th effector cells into IL-10 producers.

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          Abstract

          Secretion of the immunosuppressive cytokine interleukin (IL) 10 by effector T cells is an essential mechanism of self-limitation during infection. However, the transcriptional regulation of IL-10 expression in proinflammatory T helper (Th) 1 cells is insufficiently understood. We report a crucial role for the transcriptional regulator Blimp-1, induced by IL-12 in a STAT4-dependent manner, in controlling IL-10 expression in Th1 cells. Blimp-1 deficiency led to excessive inflammation during Toxoplasma gondii infection with increased mortality. IL-10 production from Th1 cells was strictly dependent on Blimp-1 but was further enhanced by the synergistic function of c-Maf, a transcriptional regulator of IL-10 induced by multiple factors, such as the Notch pathway. We found Blimp-1 expression, which was also broadly induced by IL-27 in effector T cells, to be antagonized by transforming growth factor (TGF) β. While effectively blocking IL-10 production from Th1 cells, TGF-β shifted IL-10 regulation from a Blimp-1-dependent to a Blimp-1-independent pathway in IL-27-induced Tr1 (T regulatory 1) cells. Our findings further illustrate how IL-10 regulation in Th cells relies on several transcriptional programs that integrate various signals from the environment to fine-tune expression of this critical immunosuppressive cytokine.

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          Most cited references 49

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          Gene ontology: tool for the unification of biology. The Gene Ontology Consortium.

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            Interleukin-10 and the interleukin-10 receptor.

            Interleukin-10 (IL-10), first recognized for its ability to inhibit activation and effector function of T cells, monocytes, and macrophages, is a multifunctional cytokine with diverse effects on most hemopoietic cell types. The principal routine function of IL-10 appears to be to limit and ultimately terminate inflammatory responses. In addition to these activities, IL-10 regulates growth and/or differentiation of B cells, NK cells, cytotoxic and helper T cells, mast cells, granulocytes, dendritic cells, keratinocytes, and endothelial cells. IL-10 plays a key role in differentiation and function of a newly appreciated type of T cell, the T regulatory cell, which may figure prominently in control of immune responses and tolerance in vivo. Uniquely among hemopoietic cytokines, IL-10 has closely related homologs in several virus genomes, which testify to its crucial role in regulating immune and inflammatory responses. This review highlights findings that have advanced our understanding of IL-10 and its receptor, as well as its in vivo function in health and disease.
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              The regulation of IL-10 production by immune cells.

              Interleukin-10 (IL-10), a cytokine with anti-inflammatory properties, has a central role in infection by limiting the immune response to pathogens and thereby preventing damage to the host. Recently, an increasing interest in how IL10 expression is regulated in different immune cells has revealed some of the molecular mechanisms involved at the levels of signal transduction, epigenetics, transcription factor binding and gene activation. Understanding the specific molecular events that regulate the production of IL-10 will help to answer the remaining questions that are important for the design of new strategies of immune intervention.
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                Author and article information

                Journal
                J. Exp. Med.
                The Journal of experimental medicine
                Rockefeller University Press
                1540-9538
                0022-1007
                Aug 25 2014
                : 211
                : 9
                Affiliations
                [1 ] German Rheumatism Research Centre Berlin, an Institute of the Leibniz-Association, 10117 Berlin, Germany Department of Rheumatology and Clinical Immunology, Medical Clinic I, Gastroenterology, and Department of Microbiology and Hygiene, Charité University Hospital, 10117 Berlin, Germany.
                [2 ] German Rheumatism Research Centre Berlin, an Institute of the Leibniz-Association, 10117 Berlin, Germany.
                [3 ] Miltenyi Biotec GmbH, 51429 Bergisch Gladbach, Germany.
                [4 ] Department of Rheumatology and Clinical Immunology, Medical Clinic I, Gastroenterology, and Department of Microbiology and Hygiene, Charité University Hospital, 10117 Berlin, Germany.
                [5 ] Leibniz Research Institute for Environmental Medicine, 40225 Düsseldorf, Germany.
                [6 ] Academy of Immunology and Microbiology (AIM), Institute for Basic Science (IBS) Pohang, Division of Integrative Biosciences and Biotechnology, Pohang University of Science and Technology, Pohang, Republic of Korea.
                [7 ] German Rheumatism Research Centre Berlin, an Institute of the Leibniz-Association, 10117 Berlin, Germany alexander.scheffold@charite.de saschar@gene.com.
                [8 ] German Rheumatism Research Centre Berlin, an Institute of the Leibniz-Association, 10117 Berlin, Germany Department of Rheumatology and Clinical Immunology, Medical Clinic I, Gastroenterology, and Department of Microbiology and Hygiene, Charité University Hospital, 10117 Berlin, Germany alexander.scheffold@charite.de saschar@gene.com.
                Article
                jem.20131548
                10.1084/jem.20131548
                4144744
                25073792

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