Mrózek E, Anderson P, Caligiuri M A
Department of Hematologic Oncology, Roswell Park Cancer Institute, Buffalo, NY 14263, USA.
Blood. 1996 Apr 1;87(7):2632-40.
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.
人类自然杀伤（NK）细胞是源自骨髓（BM）的CD2 + CD16 + CD56 + 大颗粒淋巴细胞（LGL），缺乏CD3但含有T细胞受体ζ链（ζ-TCR）。在几种实验动物模型的感染早期，NK细胞可提供必需的干扰素-γ（IFN-γ）。多项研究表明，人CD3 - CD56 + NK细胞可从在白细胞介素-2（IL-2）和异基因饲养细胞层存在的情况下培养的源自BM的CD34 + 造血祖细胞（HPC）中获得，或从IL-2和其他造血生长因子如c-kit配体（KL）中获得。未能在BM基质中检测到IL-2基因产物以及在IL-2缺陷小鼠中存在NK细胞表明，除IL-2外的其他细胞因子可能参与体内HPC向NK细胞的分化。IL-15是一种细胞因子，虽然在IL-2中缺乏任何序列同源性，但可通过IL-2受体激活细胞。在此我们表明，人BM基质细胞表达IL-15转录本，长期BM基质细胞培养物的上清液含有IL-15蛋白。在体外，CD3 - CD56 + NK细胞可从在无IL-2、基质细胞或其他细胞因子的情况下补充有IL-15的CD34 + HPC的21天培养物中获得。向这些培养物中添加KL对CD3 - CD56 + 细胞毒性效应细胞的分化没有影响，但极大地增强了它们的扩增。这些细胞中的大多数缺乏CD2和CD16，但确实表达ζ-TCR。与外周血中发现的NK细胞相似，发现在IL-15存在下生长的CD2 - CD16 - CD56 + NK细胞是对单核细胞衍生细胞因子有反应的IFN-γ的有效产生者。因此，IL-15与KL一样，似乎由BM基质细胞产生。IL-15可诱导CD34 + HPC分化为CD3 - CD56 + NK细胞，而KL可放大此过程。因此，IL-15可能是体内NK细胞分化的生理相关配体。
