Toll-Like Receptor Engagement Enhances the Immunosuppressive Properties of Human Bone Marrow-Derived Mesenchymal Stem Cells by Inducing Indoleamine-2,3-dioxygenase-1 via Interferon-β and Protein Kinase R

Authors

  • Christiane A. Opitz,

    1. Department of Neurooncology, University Hospital of Heidelberg and German Cancer Research Center, Heidelberg, Germany
    2. Department of General Neurology and Hertie Institute for Clinical Brain Research, University of Tübingen, Tübingen, Germany
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  • Ulrike M. Litzenburger,

    1. Department of Neurooncology, University Hospital of Heidelberg and German Cancer Research Center, Heidelberg, Germany
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  • Christian Lutz,

    1. Heidelberg-Pharma AG, Ladenburg, Germany
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  • Tobias V. Lanz,

    1. Department of General Neurology and Hertie Institute for Clinical Brain Research, University of Tübingen, Tübingen, Germany
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  • Isabel Tritschler,

    1. Department of General Neurology and Hertie Institute for Clinical Brain Research, University of Tübingen, Tübingen, Germany
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  • Alexandra Köppel,

    1. Institute of Human Genetics, University of Heidelberg, Heidelberg, Germany
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  • Eva Tolosa,

    1. Department of General Neurology and Hertie Institute for Clinical Brain Research, University of Tübingen, Tübingen, Germany
    2. Department of Neuroimmunology and Clinical Multiple Sclerosis Research, Center for Molecular Neurobiology Hamburg (ZMNH), Hamburg, Germany
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  • Maik Hoberg,

    1. Department of Orthopedics, Technical University of Munich, Munich, Germany
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  • Jan Anderl,

    1. Heidelberg-Pharma AG, Ladenburg, Germany
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  • Wilhelm K. Aicher,

    1. Center for Regenerative Medicine, University of Tübingen, Tübingen, Germany
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  • Michael Weller,

    1. Department of General Neurology and Hertie Institute for Clinical Brain Research, University of Tübingen, Tübingen, Germany
    2. Department of Neurology, University Hospital Zurich, Zurich, Switzerland
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  • Wolfgang Wick,

    1. Department of Neurooncology, University Hospital of Heidelberg and German Cancer Research Center, Heidelberg, Germany
    2. Department of General Neurology and Hertie Institute for Clinical Brain Research, University of Tübingen, Tübingen, Germany
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  • Michael Platten

    Corresponding author
    1. Department of Neurooncology, University Hospital of Heidelberg and German Cancer Research Center, Heidelberg, Germany
    2. Department of General Neurology and Hertie Institute for Clinical Brain Research, University of Tübingen, Tübingen, Germany
    • Department of Neurooncology, University Hospital Heidelberg, INF 400 and German Cancer Research Center, INF 280, Heidelberg, Germany
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    • Ph: +49-6221-56-7075; Fax: +49-6221-56-7554


  • Author contributions: C.A.O.: designed and performed research, analyzed data, and wrote the article; U.M.L. and C.L.: performed research and analyzed data; T.V.L., I.T., and A.K.: performed research; E.T.: designed research and contributed vital new reagents; M.H., J.A., and W.K.A.: contributed vital new reagents and performed research; M.W.: designed research; W.W.: designed research and wrote the article; M.P.: designed research, analyzed data, and wrote the article.

  • First published online in STEM CELLSExpress January 15, 2009.

Abstract

Mesenchymal stem cells (MSC) display unique suppressive properties on T-cell immunity, thus representing an attractive vehicle for the treatment of conditions associated with harmful T-cell responses such as organ-specific autoimmunity and graft-versus-host disease. Toll-like receptors (TLR) are primarily expressed on antigen-presenting cells and recognize conserved pathogen-derived components. Ligation of TLR activates multiple innate and adaptive immune response pathways to eliminate and protect against invading pathogens. In this work, we show that TLR expressed on human bone marrow-derived MSC enhanced the immunosuppressive phenotype of MSC. Immunosuppression mediated by TLR was dependent on the production of immunosuppressive kynurenines by the tryptophan-degrading enzyme indoleamine-2,3-dioxygenase-1 (IDO1). Induction of IDO1 by TLR involved an autocrine interferon (IFN)-β signaling loop, which was dependent on protein kinase R (PKR), but independent of IFN-γ. These data define a new role for TLR in MSC immunobiology, which is to augment the immunosuppressive properties of MSC in the absence of IFN-γ rather than inducing proinflammatory immune response pathways. PKR and IFN-β play a central, previously unidentified role in orchestrating the production of immunosuppressive kynurenines by MSC. STEM CELLS 2009;27:909–919

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