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A Potential Protein Adjuvant Derived from Mycobacterium tuberculosis Rv0652 Enhances Dendritic Cells-Based Tumor Immunotherapy

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      Abstract

      A key factor in dendritic cell (DC)-based tumor immunotherapy is the identification of an immunoadjuvant capable of inducing DC maturation to enhance cellular immunity. The efficacy of a 50S ribosomal protein L7/L12 (rplL) from Mycobacterium tuberculosis Rv0652, as an immunoadjuvant for DC-based tumor immunotherapy, and its capacity for inducing DC maturation was investigated. In this study, we showed that Rv0652 is recognized by Toll-like receptor 4 (TLR4) to induce DC maturation, and pro-inflammatory cytokine production (TNF-alpha, IL-1beta, and IL-6) that is partially modulated by both MyD88 and TRIF signaling pathways. Rv0652-activated DCs could activate naïve T cells, effectively polarize CD4+ and CD8+ T cells to secrete IFN-gamma, and induce T cell-mediated-cytotoxicity. Immunization of mice with Rv0652-stimulated ovalbumin (OVA)-pulsed DCs resulted in induction of a potent OVA-specific CD8+ T cell response, slowed tumor growth, and promoted long-term survival in a murine OVA-expressing E.G7 thymoma model. These findings suggest that Rv0652 enhances the polarization of T effector cells toward a Th1 phenotype through DC maturation, and that Rv0652 may be an effective adjuvant for enhancing the therapeutic response to DC-based tumor immunotherapy.

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      Most cited references 44

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      Dendritic cells and the control of immunity.

      B and T lymphocytes are the mediators of immunity, but their function is under the control of dendritic cells. Dendritic cells in the periphery capture and process antigens, express lymphocyte co-stimulatory molecules, migrate to lymphoid organs and secrete cytokines to initiate immune responses. They not only activate lymphocytes, they also tolerize T cells to antigens that are innate to the body (self-antigens), thereby minimizing autoimmune reactions. Once a neglected cell type, dendritic cells can now be readily obtained in sufficient quantities to allow molecular and cell biological analysis. With knowledge comes the realization that these cells are a powerful tool for manipulating the immune system.
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        Toll-like receptor control of the adaptive immune responses.

        Recognition of microbial infection and initiation of host defense responses is controlled by multiple mechanisms. Toll-like receptors (TLRs) have recently emerged as a key component of the innate immune system that detect microbial infection and trigger antimicrobial host defense responses. TLRs activate multiple steps in the inflammatory reactions that help to eliminate the invading pathogens and coordinate systemic defenses. In addition, TLRs control multiple dendritic cell functions and activate signals that are critically involved in the initiation of adaptive immune responses. Recent studies have provided important clues about the mechanisms of TLR-mediated control of adaptive immunity orchestrated by dendritic cell populations in distinct anatomical locations.
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          Role of adaptor TRIF in the MyD88-independent toll-like receptor signaling pathway.

          Stimulation of Toll-like receptors (TLRs) triggers activation of a common MyD88-dependent signaling pathway as well as a MyD88-independent pathway that is unique to TLR3 and TLR4 signaling pathways leading to interferon (IFN)-beta production. Here we disrupted the gene encoding a Toll/IL-1 receptor (TIR) domain-containing adaptor, TRIF. TRIF-deficient mice were defective in both TLR3- and TLR4-mediated expression of IFN-beta and activation of IRF-3. Furthermore, inflammatory cytokine production in response to the TLR4 ligand, but not to other TLR ligands, was severely impaired in TRIF-deficient macrophages. Mice deficient in both MyD88 and TRIF showed complete loss of nuclear factor kappa B activation in response to TLR4 stimulation. These findings demonstrate that TRIF is essential for TLR3- and TLR4-mediated signaling pathways facilitating mammalian antiviral host defense.
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            Author and article information

            Affiliations
            [1 ]Department of Immunology, Lab of Dendritic Cell Differentiation & Regulation, School of Medicine, Konkuk University, Chungju, South Korea
            [2 ]Department of Microbiology, Institute for Immunology and Immunological Diseases, Brain Korea 21 PLUS Project for Medical Science, Yonsei University College of Medicine, Seoul, South Korea
            [3 ]Department of Physiology, College of Medicine, Korea University, Seoul, South Korea
            [4 ]Department of Physiology, School of Medicine, Kangwon National University, Chuncheon, South Korea
            [5 ]Department of Biochemistry, College of Medicine, Seonam University, Namwon, Jeonbuk, South Korea
            [6 ]Division of Biotechnology, Advanced Institute of Environment and Bioscience, College of Environmental & Bioresources Sciences, Chonbuk National University, Iksan, South Korea
            [7 ]Department of Pharmacology, College of Medicine, Chung-Ang University, Seoul, South Korea
            [8 ]Department of Agricultural Biotechnology, and Research Institute for Agriculture and Life Sciences, Seoul National University, Seoul, South Korea
            Shanghai Jiao Tong University School of Medicine, China
            Author notes

            Competing Interests: The authors have declared that no competing interests exist.

            Performed the experiments: SJL SJS MHL WSP BYS JHP HWK IDJ YMP. Analyzed the data: SJL SJS MGL YKS CHY IDJ YMP. Contributed reagents/materials/analysis tools: SJS MGL THK YKS CHY IDJ YMP. Wrote the paper: MGL CHY IDJ YMP.

            Contributors
            Role: Editor
            Journal
            PLoS One
            PLoS ONE
            plos
            plosone
            PLoS ONE
            Public Library of Science (San Francisco, USA )
            1932-6203
            2014
            7 August 2014
            : 9
            : 8
            25102137
            4125215
            PONE-D-13-54738
            10.1371/journal.pone.0104351
            (Editor)

            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.

            Counts
            Pages: 11
            Funding
            This study was supported by a National Research Foundation of Korea (NRF) grant funded by the Korean Government (NRF-2012R1A2A1A03008433, NRF-2012R1A1A4A01007325, and NRF-2011-0028573), a grant from the National R&D Program for Cancer Control, Ministry for Health and Welfare, Republic of Korea (1120390). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.
            Categories
            Research Article
            Biology and Life Sciences
            Cell Biology
            Cellular Types
            Animal Cells
            Immune Cells
            Molecular Cell Biology
            Immunology
            Immunity
            Immune Activation
            Antigen Processing and Recognition
            Clinical Immunology
            Immune Response
            Immune System
            Immunomodulation
            Vaccination and Immunization
            Microbiology
            Physiology
            Immune Physiology
            Medicine and Health Sciences

            Uncategorized

            Comments

            added an editorial note to Cancer Immunotherapy
            This article was selected by ScienceOpen Consulting Editor, Richard Gallagher, to appear in the Collection entitled Cancer Immunotherapy which can be found here http://ow.ly/Jy1HH. 1. Why this article was chosen: it shows that an immunostimulatory adjuvant enhances dendritic cell maturation, potentially generating antitumor immune responses in patients that are as effective as those in animal models. 2. What this article shows: a mycobacteria protein, rRv0652, induces antigen-specific antitumor effects by triggering DC maturation, which improves the efficacy of DC-based antitumor immunotherapy. 3. A key quote from the article: “Notably, Rv0652 mediated a strong induction of Ag-specific, CD8+ class I-restricted, CTL responses, and E.G7 tumor regression in vivo.” 4. Corresponding authors: In Duk Jung and Yeong-Min Park are at the Department of Immunology, Konkuk University, South Korea.
            2015-02-24 02:41 UTC
            +1

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