The Comprehensive Cancer Center, The Ohio State University, Columbus, OH, USA.
Eur J Immunol. 2013 Oct;43(10):2750-5. doi: 10.1002/eji.201243116. Epub 2013 Jul 8.
Activation of the fibromyalgia syndrome-like tyrosine kinase 3 (FLT3) by its ligand, FLT3 ligand (FL), strongly augments the development of natural killer (NK) cells from human CD34⁺ hematopoietic progenitor cells (HPCs) in the presence of IL-15, compared with NK-cell development in the presence of IL-15 alone. In this study, we observed that blocking the receptor tyrosine kinase Axl/Gas6 pathway with a soluble Axl-IgG1 Fc fusion protein (Axl-Fc) in the presence of FL significantly diminished the absolute number of CD3⁻ CD56⁺ NK cells derived from human CD34⁺ HPCs. Axl-Fc reduced the expression levels of the IL-2/15 receptor β chain (CD122) and γ chain (CD132) induced by activation of FLT3 and consequently reduced the frequency of NK precursor cells responding to IL-15. Furthermore, Axl-Fc diminished FL-induced FLT3 phosphorylation and impeded the physical interaction between Axl and FLT3 in CD34⁺ HPCs. Collectively, our data suggest that the Axl/Gas6 pathway contributes to normal human NK-cell development at least in part via its positive regulatory effect on FLT3 signaling in CD34⁺ HPCs.
纤维肌痛综合征样酪氨酸激酶 3（FLT3）与其配体 FLT3 配体（FL）的激活，在白细胞介素 15（IL-15）存在的情况下，强烈增强了人类 CD34⁺造血祖细胞（HPC）中自然杀伤（NK）细胞的发育，而在单独存在 IL-15 的情况下，NK 细胞的发育则增强。在这项研究中，我们观察到，在存在 FL 的情况下，用可溶性 Axl-IgG1 Fc 融合蛋白（Axl-Fc）阻断受体酪氨酸激酶 Axl/Gas6 通路，可显著减少源自人类 CD34⁺HPC 的 CD3⁻CD56⁺NK 细胞的绝对数量。Axl-Fc 降低了由 FLT3 激活诱导的 IL-2/15 受体 β 链（CD122）和 γ 链（CD132）的表达水平，从而降低了对 IL-15 有反应的 NK 前体细胞的频率。此外，Axl-Fc 减弱了 FL 诱导的 FLT3 磷酸化，并阻碍了 CD34⁺HPC 中 Axl 和 FLT3 之间的物理相互作用。总的来说，我们的数据表明，Axl/Gas6 通路至少部分通过其对 CD34⁺HPC 中 FLT3 信号的正向调节作用，有助于正常的人类 NK 细胞发育。
