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Regulatory T cells control toxicity in a humanized model of IL-2 therapy

Author

Listed:
  • Yan Li

    (Institut Pasteur, Innate Immunity Unit, Immunology Department
    Inserm U1223)

  • Helene Strick-Marchand

    (Institut Pasteur, Innate Immunity Unit, Immunology Department
    Inserm U1223)

  • Ai Ing Lim

    (Institut Pasteur, Innate Immunity Unit, Immunology Department
    Inserm U1223)

  • Jiazi Ren

    (Key Laboratory of Molecular Virology and Immunology, CAS Center for Excellence in Molecular Cell Science, Unit of Molecular Immunology, Institut Pasteur of Shanghai, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences)

  • Guillemette Masse-Ranson

    (Institut Pasteur, Innate Immunity Unit, Immunology Department
    Inserm U1223)

  • Li

    (Key Laboratory of Molecular Virology and Immunology, CAS Center for Excellence in Molecular Cell Science, Unit of Molecular Immunology, Institut Pasteur of Shanghai, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences
    Shanghai Institute of Immunology, Shanghai JiaoTong University School of Medicine)

  • Gregory Jouvion

    (Institut Pasteur, Human Histopathology and Animal Models Unit)

  • Lars Rogge

    (Institut Pasteur, Immunoregulation Unit, Immunology Department)

  • Sophie Lucas

    (de Duve Institute, Université Catholique de Louvain, and WELBIO)

  • Li

    (Key Laboratory of Molecular Virology and Immunology, CAS Center for Excellence in Molecular Cell Science, Unit of Molecular Immunology, Institut Pasteur of Shanghai, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences
    Shanghai Institute of Immunology, Shanghai JiaoTong University School of Medicine)

  • James P. Di Santo

    (Institut Pasteur, Innate Immunity Unit, Immunology Department
    Inserm U1223)

Abstract

While patient selection and clinical management have reduced high-dose IL-2 (HDIL2) immunotherapy toxicities, the immune mechanisms that underlie HDIL2-induced morbidity remain unclear. Here we show that dose-dependent morbidity and mortality of IL-2 immunotherapy can be modeled in human immune system (HIS) mice. Depletion of human T cell subsets during the HDIL2 treatment reduces toxicity, pointing to the central function of T cells. Preferential expansion of effector T cells secondary to defective suppressive capacity of regulatory T (Treg) cells after HDIL2 therapy further underscores the importance of Treg in the maintenance of immune tolerance. IL-2 toxicity is induced by selective depletion or inhibition of Treg after LDIL2 therapy, and is ameliorated in HDIL2-treated HIS mice receiving the PIM-1 kinase inhibitor, Kaempferol. Modeling IL-2 pathophysiology in HIS mice offers a means to understand the functions of effector and regulatory T cells in immune-mediated toxicities associated with cancer immunotherapy.

Suggested Citation

  • Yan Li & Helene Strick-Marchand & Ai Ing Lim & Jiazi Ren & Guillemette Masse-Ranson & Li & Gregory Jouvion & Lars Rogge & Sophie Lucas & Li & James P. Di Santo, 2017. "Regulatory T cells control toxicity in a humanized model of IL-2 therapy," Nature Communications, Nature, vol. 8(1), pages 1-12, December.
    • Handle: RePEc:nat:natcom:v:8:y:2017:i:1:d:10.1038_s41467-017-01570-9
    DOI: 10.1038/s41467-017-01570-9
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