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    IL-15 trans-presentation promotes human NK cell development and differentiation in vivo

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    340
    Author
    Huntington, ND; Legrand, N; Alves, NL; Jaron, B; Weijer, K; Plet, A; Corcuff, E; Mortier, E; Jacques, Y; Spits, H; ...
    Date
    2009-01-16
    Source Title
    Journal of Experimental Medicine
    Publisher
    ROCKEFELLER UNIV PRESS
    University of Melbourne Author/s
    Huntington, Nicholas
    Affiliation
    Medical Biology (W.E.H.I.)
    Metadata
    Show full item record
    Document Type
    Journal Article
    Citations
    Huntington, N. D., Legrand, N., Alves, N. L., Jaron, B., Weijer, K., Plet, A., Corcuff, E., Mortier, E., Jacques, Y., Spits, H. & Di Santo, J. P. (2009). IL-15 trans-presentation promotes human NK cell development and differentiation in vivo. JOURNAL OF EXPERIMENTAL MEDICINE, 206 (1), pp.25-34. https://doi.org/10.1084/jem.20082013.
    Access Status
    Open Access
    URI
    http://hdl.handle.net/11343/260201
    DOI
    10.1084/jem.20082013
    Abstract
    The in vivo requirements for human natural killer (NK) cell development and differentiation into cytotoxic effectors expressing inhibitory receptors for self-major histocompatibility complex class I (MHC-I; killer Ig-like receptors [KIRs]) remain undefined. Here, we dissect the role of interleukin (IL)-15 in human NK cell development using Rag2(-/-)gamma c(-/-) mice transplanted with human hematopoietic stem cells. Human NK cell reconstitution was intrinsically low in this model because of the poor reactivity to mouse IL-15. Although exogenous human IL-15 (hIL-15) alone made little improvement, IL-15 coupled to IL-15 receptor alpha (IL-15R alpha) significantly augmented human NK cells. IL-15-IL-15R alpha complexes induced extensive NK cell proliferation and differentiation, resulting in accumulation of CD16(+)KIR(+) NK cells, which was not uniquely dependent on enhanced survival or preferential responsiveness of this subset to IL-15. Human NK cell differentiation in vivo required hIL-15 and progressed in a linear fashion from CD56(hi)CD16(-)KIR(-) to CD56(lo)CD16(+)KIR(-), and finally to CD56(lo)CD16(+)KIR(+). These data provide the first evidence that IL-15 trans-presentation regulates human NK cell homeostasis. Use of hIL-15 receptor agonists generates a robust humanized immune system model to study human NK cells in vivo. IL-15 receptor agonists may provide therapeutic tools to improve NK cell reconstitution after bone marrow transplants, enhance graft versus leukemia effects, and increase the pool of IL-15-responsive cells during immunotherapy strategies.

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