Autonomous and extrinsic regulation of thymopoiesis inhuman immune system (HIS) mice

Authors

  • Nicholas D. Huntington,

    Corresponding author
    1. Innate Immunity Unit, Immunology Department, Institut Pasteur, Paris, France
    2. INSERM U668, Paris, France
    3. Part of the Human Vaccine Consortium, “Grand Challenges in Global Health 4: devise reliable testing systems for new vaccines” (http://www.hv-consortium.org/), USA
    • Innate Immunity Unit, Immunology Department, Institut Pasteur, Paris 75724, France Fax: +33-1-40-61-35-10
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  • Nuno L. Alves,

    1. Innate Immunity Unit, Immunology Department, Institut Pasteur, Paris, France
    2. INSERM U668, Paris, France
    3. Cell Activation and Gene Expression Group, Instituto de Biologia Molecular e Celular, Porto, Portugal
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  • Nicolas Legrand,

    1. Part of the Human Vaccine Consortium, “Grand Challenges in Global Health 4: devise reliable testing systems for new vaccines” (http://www.hv-consortium.org/), USA
    2. Department of Cell Biology and Histology, Academic Medical Center of the University of Amsterdam (AMC-UvA), Center for Immunology Amsterdam (CIA), Amsterdam, The Netherlands
    Current affiliation:
    1. AIMM Therapeutics, Amsterdam, The Netherlands
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  • Annick Lim,

    1. INSERM U668, Paris, France
    2. Lymphocyte Development Unit, Institut Pasteur, Paris, France
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  • Hélène Strick-Marchand,

    1. Innate Immunity Unit, Immunology Department, Institut Pasteur, Paris, France
    2. INSERM U668, Paris, France
    3. Part of the Human Vaccine Consortium, “Grand Challenges in Global Health 4: devise reliable testing systems for new vaccines” (http://www.hv-consortium.org/), USA
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  • Ariane Plet,

    1. INSERM, Groupe de Recherche Cytokines et Récepteurs, Institut de Biologie, Univ Nantes, Nantes, France
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  • Kees Weijer,

    1. Part of the Human Vaccine Consortium, “Grand Challenges in Global Health 4: devise reliable testing systems for new vaccines” (http://www.hv-consortium.org/), USA
    2. Department of Cell Biology and Histology, Academic Medical Center of the University of Amsterdam (AMC-UvA), Center for Immunology Amsterdam (CIA), Amsterdam, The Netherlands
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  • Yannick Jacques,

    1. INSERM, Groupe de Recherche Cytokines et Récepteurs, Institut de Biologie, Univ Nantes, Nantes, France
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  • Hergen Spits,

    1. Part of the Human Vaccine Consortium, “Grand Challenges in Global Health 4: devise reliable testing systems for new vaccines” (http://www.hv-consortium.org/), USA
    2. Department of Cell Biology and Histology, Academic Medical Center of the University of Amsterdam (AMC-UvA), Center for Immunology Amsterdam (CIA), Amsterdam, The Netherlands
    Current affiliation:
    1. AIMM Therapeutics, Amsterdam, The Netherlands
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  • James P. Di Santo

    Corresponding author
    1. Innate Immunity Unit, Immunology Department, Institut Pasteur, Paris, France
    2. INSERM U668, Paris, France
    3. Part of the Human Vaccine Consortium, “Grand Challenges in Global Health 4: devise reliable testing systems for new vaccines” (http://www.hv-consortium.org/), USA
    • Innate Immunity Unit, Immunology Department, Institut Pasteur, Paris 75724, France
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Abstract

Human Immune System (HIS) mice represent a novel biotechnology platform to dissect human haematopoiesis and immune responses. However, the limited human T-cell development that is observed in HIS mice restricts its utility for these applications. Here, we address whether reduced thymopoiesis in HIS mice reflects an autonomous defect in T-cell precursors and/or a defect in the murine thymic niche. Human thymocyte precursors seed the mouse thymus and their reciprocal interactions with murine thymic epithelial cells (TECs) led to both T-cell and TEC maturation. The human thymocyte subsets observed in HIS mice demonstrated survival, proliferative and phenotypic characteristics of their normal human counterparts, suggesting that the intrinsic developmental program of human thymocytes unfolds normally in this xenograft setting. We observed that exogenous administration of human IL-15/IL-15Rα agonistic complexes induced the survival, proliferation and absolute numbers of immature human thymocyte subsets, without any obvious effect on cell-surface phenotype or TCR Vβ usage amongst the newly selected mature single-positive (SP) thymocytes. Finally, when IL-15 was administered early after stem cell transplantation, we noted accelerated thymopoiesis resulting in the more rapid appearance of peripheral naïve T cells. Our results highlight the functional capacity of murine thymic stroma cells in promoting human thymopoiesis in HIS mice but suggest that the “cross-talk” between murine thymic stroma and human haematopoietic precursors may be suboptimal. As IL-15 immunotherapy promotes early thymopoiesis, this novel approach could be used to reduce the period of T-cell immunodeficiency in the post-transplant clinical setting.

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