IL-15 Can Substitute for the Marrow Microenvironment in the Differentiation of Natural Killer Cells

NK cells require an intact bone marrow microenvironment to acquire lytic function. In mice rendered osteopetrotic by 17β-estradiol treatment, NK1.1 positive cells are arrested in a nonlytic state. Culture with as little as 2 ng/ml of murine IL-15 (mIL-15), a cytokine produced by macrophages and stromal cells, causes these immature NK1.1⁺ cells to acquire lytic activity. By contrast, approximately 10- to 50-fold greater amount of mIL-2 was required to induce similar level of cytotoxicity. After culture with mIL-15, the relatively low expression of B220, CD11b, and Ly-49 molecules on immature NK1.1⁺ cells was increased to levels comparable to those of mature splenic NK1.1⁺ cells. mIL-15 also caused a greater expansion of NK1.1⁺CD3^- cells as compared with NK1.1⁺CD3⁺ cells. We conclude that IL-15 is a specific maturation factor for NK cells and that it can mimic the marrow microenvironment in vitro.