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      Blimp-1-Dependent IL-10 Production by Tr1 Cells Regulates TNF-Mediated Tissue Pathology

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          Abstract

          Tumor necrosis factor (TNF) is critical for controlling many intracellular infections, but can also contribute to inflammation. It can promote the destruction of important cell populations and trigger dramatic tissue remodeling following establishment of chronic disease. Therefore, a better understanding of TNF regulation is needed to allow pathogen control without causing or exacerbating disease. IL-10 is an important regulatory cytokine with broad activities, including the suppression of inflammation. IL-10 is produced by different immune cells; however, its regulation and function appears to be cell-specific and context-dependent. Recently, IL-10 produced by Th1 (Tr1) cells was shown to protect host tissues from inflammation induced following infection. Here, we identify a novel pathway of TNF regulation by IL-10 from Tr1 cells during parasitic infection. We report elevated Blimp-1 mRNA levels in CD4 + T cells from visceral leishmaniasis (VL) patients, and demonstrate IL-12 was essential for Blimp-1 expression and Tr1 cell development in experimental VL. Critically, we show Blimp-1-dependent IL-10 production by Tr1 cells prevents tissue damage caused by IFNγ-dependent TNF production. Therefore, we identify Blimp-1-dependent IL-10 produced by Tr1 cells as a key regulator of TNF-mediated pathology and identify Tr1 cells as potential therapeutic tools to control inflammation.

          Author Summary

          Many parasitic diseases are associated with the generation of potent inflammatory responses. These are often needed to control infection, but can also cause tissue damage if not appropriately regulated. IL-10 has emerged as an important immune regulator that protects tissues by dampening inflammation. Recently, some T cells that initially produce inflammatory cytokines have been found to start producing IL-10 as a mechanism of auto-regulation. We identified an important transcriptional regulator called B lymphocyte-induced maturation protein 1 (Blimp-1), which promotes IL-10 production by IFNγ-producing CD4 + T (Tr1) cells during malaria and visceral leishmaniasis, two important diseases caused by protozoan parasites. We found that Tr1 cell-derived IL-10 suppressed anti-parasitic immunity, but played a critical role in preventing tissue damage caused by the potent pro-inflammatory cytokine TNF. Specifically, IL-10 protected macrophages from TNF-mediated destruction, and this enabled lymphocytes to continue to migrate to regions in the spleen where T and B cell responses are generated. These findings allow us to better understand how parasites persist in a host, but also identify new opportunities to control inflammation to prevent disease.

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          Most cited references 88

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          Regulatory T cells and immune tolerance.

          Regulatory T cells (Tregs) play an indispensable role in maintaining immunological unresponsiveness to self-antigens and in suppressing excessive immune responses deleterious to the host. Tregs are produced in the thymus as a functionally mature subpopulation of T cells and can also be induced from naive T cells in the periphery. Recent research reveals the cellular and molecular basis of Treg development and function and implicates dysregulation of Tregs in immunological disease.
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            Differentiation of effector CD4 T cell populations (*).

            CD4 T cells play critical roles in mediating adaptive immunity to a variety of pathogens. They are also involved in autoimmunity, asthma, and allergic responses as well as in tumor immunity. During TCR activation in a particular cytokine milieu, naive CD4 T cells may differentiate into one of several lineages of T helper (Th) cells, including Th1, Th2, Th17, and iTreg, as defined by their pattern of cytokine production and function. In this review, we summarize the discovery, functions, and relationships among Th cells; the cytokine and signaling requirements for their development; the networks of transcription factors involved in their differentiation; the epigenetic regulation of their key cytokines and transcription factors; and human diseases involving defective CD4 T cell differentiation.
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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

                Contributors
                Role: Editor
                Journal
                PLoS Pathog
                PLoS Pathog
                plos
                plospath
                PLoS Pathogens
                Public Library of Science (San Francisco, CA USA )
                1553-7366
                1553-7374
                14 January 2016
                January 2016
                : 12
                : 1
                Affiliations
                [1 ]QIMR Berghofer Medical Research Institute, Brisbane, Australia
                [2 ]University of Queensland, School of Medicine, Brisbane, Australia
                [3 ]Netaji Subhas Institute of Technology, New Delhi, India
                [4 ]Queensland University of Technology, Institute of Health and Biomedical Innovation, Brisbane, Australia
                [5 ]Griffith University, Institute of Glycomics, Gold Coast, Australia
                [6 ]Griffith University, School of Natural Sciences, Nathan, Australia
                [7 ]University of Manchester, Faculty of Life Sciences, Manchester, United Kingdom
                [8 ]Walter and Eliza Hall Medical Research Institute, Division of Molecular Immunology, Melbourne, Australia
                [9 ]The University of Melbourne, Department of Medical Biology, Melbourne, Australia
                [10 ]Banaras Hindu University, Institute of Medical Sciences, Varanasi, Uttar Pradesh, India
                University of Pennsylvania, UNITED STATES
                Author notes

                The authors have declared that no competing interests exist.

                Conceived and designed the experiments: MMdO AK CRE. Performed the experiments: MMdO RK FdLR FHA MS RJF PTB SEB LB SSN CLE. Analyzed the data: LB MJS AH GRH SS AK CRE. Contributed reagents/materials/analysis tools: WM EC SLN. Wrote the paper: MMdO CRE.

                Article
                PPATHOGENS-D-15-02210
                10.1371/journal.ppat.1005398
                4713066
                26765224
                © 2016 Montes de Oca et al

                This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

                Page count
                Figures: 8, Tables: 0, Pages: 21
                Product
                Funding
                This work was made possible through Queensland State Government Funding, Victorian State Government Operational Infrastructure Support and Australian Government NHMRC IRIIS. Research was supported by grants and Fellowships from the National Health and Medical Research Council of Australia, funding from the Australia-India Strategic Research fund made available by the Australian government Department of Innovation, Industry, Science and Research and Indian Government Department of Biotechnology, and core equipment funded by the Australian Cancer Research Foundation. RK is supported by INSPIRE Fellowship, Department of Science and Technology, Indian Government. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.
                Categories
                Research Article
                Custom metadata
                All relevant data are within the paper and its Supporting Information files.

                Infectious disease & Microbiology

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