title: Role of interleukin-15 in the development of human CD56+ natural killer cells from CD34+ hematopoietic progenitor cells.
abstract: 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 zeta-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 in 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.
authors.affiliation: Department of Hematologic Oncology, Roswell Park Cancer Institute, Buffalo, NY 14263, USA.
authors.forename: E
authors.initials: E
authors.lastname: Mrózek
authors.forename: P
authors.initials: P
authors.lastname: Anderson
authors.forename: M A
authors.initials: MA
authors.lastname: Caligiuri
mesh_terms: D018952:Antigens, CD34; D001483:Base Sequence; D001853:Bone Marrow / Q000276:immunology; D001854:Bone Marrow Cells; D019002:CD56 Antigen; D002454:Cell Differentiation / Q000276:immunology; D002478:Cells, Cultured; D006412:Hematopoietic Stem Cells / Q000166:cytology* / Q000276:immunology; D006801:Humans; D016130:Immunophenotyping; D019409:Interleukin-15; D007378:Interleukins / Q000096:biosynthesis*; D007694:Killer Cells, Natural / Q000166:cytology* / Q000276:immunology; D008969:Molecular Sequence Data; D017154:Stromal Cells / Q000166:cytology / Q000276:immunology
chemical_list: D018952:Antigens, CD34; D019002:CD56 Antigen; D019409:Interleukin-15; D007378:Interleukins