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

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          Abstract

          The transcriptional regulator Blimp-1 is absolutely required for IL-10 production in Th1 cells and limits inflammatory effector T cell responses downstream of IL-12 and IL-27.

          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 38

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

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            Effector T cells control lung inflammation during acute influenza virus infection by producing IL-10

            Activated antigen-specific T cells produce a variety of effector molecules for clearing infection, but also contribute significantly to inflammation and tissue injury. Here we report an anti-inflammatory property of anti-viral CD8+ and CD4+ effector T cells (Te) in the infected periphery during acute virus infection. We find that, during acute influenza infection, IL-10 is produced in the infected lungs at high levels -- exclusively by infiltrating virus-specific Te, with CD8+ Te contributing a larger fraction of the IL-10 produced. These Te in the periphery simultaneously produce IL-10 and proinflammatory cytokines, and express lineage markers characteristic of conventional Th/c1 cells. Importantly, blocking the action of the Te-derived IL-10 results in enhanced pulmonary inflammation and lethal injury. Our results demonstrate that anti-viral Te exert regulatory functions -- that is, fine-tune the extent of lung inflammation and injury associated with influenza infection by the production of an anti-inflammatory cytokine. The potential implications of these findings for infection with highly pathogenic influenza viruses are discussed.
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              A dominant function for interleukin 27 in generating interleukin 10-producing anti-inflammatory T cells.

              Regulatory T cells (T(reg) cells) expressing the transcription factor Foxp3 are key in maintaining the balance of immune homeostasis. However, distinct induced T regulatory type 1 (Tr1) cells that lack Foxp3 expression also regulate T cell function, mainly by producing the immunosuppressive cytokine interleukin 10 (IL-10). However, the factors required for the induction of IL-10-producing suppressive T cells are not fully understood. Here we demonstrate that dendritic cells modified by T(reg) cells induced the generation of IL-10-producing Tr1 cells. The differentiation of naive CD4+ T cells into IL-10-producing cells was mediated by IL-27 produced by the T(reg) cell-modified dendritic cells, and transforming growth factor-beta amplified the generation of induced IL-10+ Tr1 cells by IL-27. Thus, IL-27 and transforming growth factor-beta promote the generation of IL-10-producing Tr1 cells.
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                Author and article information

                Journal
                J Exp Med
                J. Exp. Med
                jem
                jem
                The Journal of Experimental Medicine
                The Rockefeller University Press
                0022-1007
                1540-9538
                25 August 2014
                : 211
                : 9
                : 1807-1819
                Affiliations
                [1 ]German Rheumatism Research Centre Berlin, an Institute of the Leibniz-Association, 10117 Berlin, Germany
                [2 ]Department of Rheumatology and Clinical Immunology , [3 ]Medical Clinic I, Gastroenterology , and [4 ]Department of Microbiology and Hygiene, Charité University Hospital, 10117 Berlin, Germany
                [5 ]Miltenyi Biotec GmbH, 51429 Bergisch Gladbach, Germany
                [6 ]Leibniz Research Institute for Environmental Medicine, 40225 Düsseldorf, Germany
                [7 ]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
                Author notes
                CORRESPONDENCE A. Scheffold: alexander.scheffold@ 123456charite.de OR Sascha Rutz: saschar@ 123456gene.com

                S. Rutz and A. Scheffold contributed equally to this paper.

                S. Rutz’s present address is Genentech, Department of Immunology, South San Francisco, CA 94080

                Article
                20131548
                10.1084/jem.20131548
                4144744
                25073792
                © 2014 Neumann et al.

                This article is distributed under the terms of an Attribution–Noncommercial–Share Alike–No Mirror Sites license for the first six months after the publication date (see http://www.rupress.org/terms). After six months it is available under a Creative Commons License (Attribution–Noncommercial–Share Alike 3.0 Unported license, as described at http://creativecommons.org/licenses/by-nc-sa/3.0/).

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