| 18840707 |
Park IK, Giovenzana C, Hughes TL, Yu J, Trotta R, Caligiuri MA: The Axl/Gas6 pathway is required for optimal cytokine signaling during human natural killer cell development. Blood. 2009 Mar 12;113(11):2470-7. Epub 2008 Oct 7.
Interleukin-15 (IL-15) is essential for natural killer (NK) cell differentiation. In this study, we assessed whether the receptor tyrosine kinase Axl and its ligand, Gas6, are involved in IL-15-mediated human NK differentiation from CD34 (+) hematopoietic progenitor cells (HPCs). Blocking the Axl-Gas6 interaction with a soluble Axl fusion protein (Axl-Fc) or the vitamin K inhibitor warfarin significantly diminished the absolute number and percentage of CD3 (-) CD56 (+) NK cells derived from human CD34 (+) HPCs cultured in the presence of IL-15, probably resulting in part from reduced phosphorylation of STAT5. In addition, CD3 (-) CD56 (+) NK cells derived from culture of CD34 (+) HPCs with IL-15 and Axl-Fc had a significantly diminished capacity to express interferon-gamma or its master regulator, T-BET. Culture of CD34 (+) HPCs in the presence of c-Kit ligand and Axl-Fc resulted in a significant decrease in the frequency of NK precursor cells responding to IL-15, probably the result of reduced c-Kit phosphorylation. Collectively, our data suggest that the Axl/Gas6 pathway contributes to normal human NK-cell development, at least in part via its regulatory effects on both the IL-15 and c-Kit signaling pathways in CD34 (+) HPCs, and to functional NK-cell maturation via an effect on the master regulatory transcription factor T-BET. |
32(0,1,1,2) |