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

Abstract : The in vivo requirements for human natural killer (NK) cell development and differentiation into cytotoxic effectors expressing inhibitory receptors for self – major histocompatability 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-/- γc-/- 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 α (IL-15Rα) significantly augmented human NK cells. IL-15–IL-15Rα 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 CD56hi CD16- KIR- to CD56lo CD16+ KIR- , and finally to CD56lo 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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Nicholas D Huntington, Nicolas Legrand, Nuno L. Alves, Barbara Jaron, Kees Weijer, et al.. IL-15 trans-presentation promotes human NK cell development and differentiation in vivo. Journal of Experimental Medicine, Rockefeller University Press, 2009, 206 (1), pp.25-34. ⟨10.1084/jem.20082013⟩. ⟨inserm-02442774⟩



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