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Significance Interleukin 15 (IL-15) is essential for natural killer (NK) cell survival and proliferation. The IL-15 receptor consists of 3 subunits: the α chain and the β and common γ (γc ) chains, which are shared with the IL-2 receptor. NK cells express the β-γc chains and are activated intrans by cells presenting IL-15 bound to IL-15Rα, such as dendritic cells. We show here that the release of soluble IL-15Rα–IL-15 complex from presenting cells contributes to efficient signaling for NK cell survival, whereas uptake of the entire membrane-associated-IL-15Rα–IL-15 complex from presenting cells into NK cells contributes to proliferation. Thus, outcomes are dictated not only by signal strength, but also by location where IL-15trans -presentation occurs in NK cells.

Trans-endocytosis of intact IL-15Rα–IL-15 complex from presenting cells into NK cells favors signaling for proliferation