TableEdit

Park, IK, Giovenzana, C, Hughes, TL, Yu, J, Trotta, R and Caligiuri, MA (2009) The Axl/Gas6 pathway is required for optimal cytokine signaling during human natural killer cell development. Blood 113:2470-7

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.

PubMed PMC2656272 Online version:10.1182/blood-2008-05-157073

Antigens, CD34/metabolism; Antigens, CD34/physiology; Cell Differentiation/drug effects; Cell Differentiation/genetics; Cells, Cultured; Cytokines/pharmacology; Cytokines/physiology; Hematopoietic Stem Cells/drug effects; Hematopoietic Stem Cells/metabolism; Hematopoietic Stem Cells/physiology; Humans; Intercellular Signaling Peptides and Proteins/genetics; Intercellular Signaling Peptides and Proteins/physiology; Interleukin-15/pharmacology; Interleukin-15/physiology; K562 Cells; Killer Cells, Natural/drug effects; Killer Cells, Natural/metabolism; Killer Cells, Natural/physiology; Oncogene Proteins/genetics; Oncogene Proteins/physiology; Proto-Oncogene Proteins; Proto-Oncogene Proteins c-kit/metabolism; Proto-Oncogene Proteins c-kit/physiology; Receptor Protein-Tyrosine Kinases/genetics; Receptor Protein-Tyrosine Kinases/physiology; Signal Transduction/drug effects; Signal Transduction/genetics; Signal Transduction/physiology; T-Box Domain Proteins/physiology