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

Yan Li, Helene Strick-Marchand, Ai Ing Lim, Jiazi Ren, Guillemette Masse-Ranson, Li, Gregory Jouvion, Lars Rogge, Sophie Lucas, Li and James P. Di Santo ()
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Yan Li: Institut Pasteur, Innate Immunity Unit, Immunology Department
Helene Strick-Marchand: Institut Pasteur, Innate Immunity Unit, Immunology Department
Ai Ing Lim: Institut Pasteur, Innate Immunity Unit, Immunology Department
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
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
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
James P. Di Santo: Institut Pasteur, Innate Immunity Unit, Immunology Department

Nature Communications, 2017, vol. 8, issue 1, 1-12

Abstract: 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.

Date: 2017
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DOI: 10.1038/s41467-017-01570-9

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