Role of IL-15 and IL-15R in the differentiation of natural killer cells

NK cells require an intact marrow for differentiation, but the nature of the relevant stromal/cytokine components is unknown. IL-15, produced by macrophages and marrow stromal cell lines, activates and causes proliferation of human NK cells. These data, together with the observation that SCID and IL2 knockout mice develop NK cells, led us to test the hypothesis that IL-15 is physiologically relevant for development of NK cells. To assess this we used mice whose bone marrow was destroyed by 17-estradiol induced osteopetrosis.In such mice hemopoiesis shifts to the spleen and NK cells are arrested at an NK1.1+, nonlytic stage. Whole spleen cells or sorted NK1.1+ cells from osteopetrotic or control mice were cultured with IL-2, human(h)IL-15, or rnurine(m)IL-15 for 24 or 72 hrs.IL-2R and IL-15R share the and y chains, but each has a unique a chain. After 24 hrs, cytotoxicity of normal NK1.1+ cells was activated by both cytokines, but immature NK1.1+ cells were not activated by hIL-15, and only partially by IL-2. This defect was diminished but still present at 72 hrs. By contrast, mIL-15 caused significant and equivalent lytic activation of both sorted immature NK1.1+ cells and control NK1.1+ cells in 24 hrs. Human IL-15 can bind mIL-15Rabut not mIL-15R or y chains, whereas mIL-15 can bind all three chains and hIL-15 can activate normal but not immature NK1.1+cells. Thus non-lytic NK1.1+cells may lack expression of mlL15Ra or proper signaling through the mIL-15R complex. It is also possible that in the spleens of osteopetrotic mice there is an actual or functional deficiency of IL-15 that can be corrected readily in vitro. These data suggest that IL-15 produced in the bone marrow is involved in the differentiation of NK cells.