Role of interleukin-15 in the development of human CD56(+) natural killer cells from CD34(+) hematopoietic progenitor cells

Human natural killer (NK) cells are bone marrow (BM)-derived CD2(+)CD16(+)CD56(+) large granular lymphocytes (LGL) that lack CD3 yet contain the T-cell receptor S-chain (zeta-TCR). NK cells provide requisite interferon-gamma (IFN-gamma) during the early stages of infection in several experimental animal models, A number of studies have shown that human CD3(-)CD56(+) NK cells can be obtained from BM-derived CD34(+) hematopoietic progenitor cells (HPCs) cultured in the presence of interleukin-2 (IL-2) and an allogeneic feeder cell layer, or IL-2 and other hematopoietic growth factors such as the c-kit ligand (KL). The failure to detect the IL-2 gene product within the BM stroma and the presence of NK cells in IL-2-deficient mice suggested that cytokines other than IL-2 may participate in NK cell differentiation from HPCs in vivo. IL-15 is a cytokine which, while lacking any sequence homology to IL-2, can activate cells via the IL-2 receptor. Here we show that human BM stromal cells express the IL-15 transcript, and supernatants from long-term BM stromal cell cultures contain IL-15 protein. In vitro, CD3(-)CD56(+) NK cells can be obtained from 21-day cultures of CD34(+) HPCs supplemented with IL-15 in the absence of IL-2, stromal cells, or other cytokines. The addition of the KL to these cultures had no effect on the differentiation of the CD3(-)CD56(+) cytotoxic effector cells, but greatly enhanced their expansion, The majority of these cells lack CD2 and CD16, but do express zeta-TCR. Similar to NK cells found in peripheral blood, the CD2(-)CD16(-)CD56(+) NK cells grown in the presence of IL-15 were found to be potent producers of IFN-gamma in response to monocyte-derived cytokines. Thus IL-15, like KL, appears to be produced by BM stromal cells, IL-15 can induce CD34(+) HPCs to differentiate into CD3(-)CD56(+) NK cells, and KL can amplify this. Therefore, IL-15 may be a physiologically relevant ligand for NK cell differentiation in vivo. (C) 1996 by The American Society of Hematology.