The Axl/Gas6 pathway is required for optimal cytokine signaling during human natural killer cell development.
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.
Human Cancer Genetics Program, James Cancer Hospital and Solove Research Institute, The Ohio State University, Columbus, OH 43210, USA.
Il-Kyoo
IK
Park
Chiara
C
Giovenzana
Tiffany L
TL
Hughes
Jianhua
J
Yu
Rossana
R
Trotta
Michael A
MA
Caligiuri
D018952:Antigens, CD34 / Q000378:metabolism / Q000502:physiology; D002454:Cell Differentiation / Q000187:drug effects* / Q000235:genetics; D002478:Cells, Cultured; D016207:Cytokines / Q000494:pharmacology / Q000502:physiology; D006412:Hematopoietic Stem Cells / Q000187:drug effects / Q000378:metabolism / Q000502:physiology; D006801:Humans; D036341:Intercellular Signaling Peptides and Proteins / Q000235:genetics / Q000502:physiology*; D019409:Interleukin-15 / Q000494:pharmacology* / Q000502:physiology; D020014:K562 Cells; D007694:Killer Cells, Natural / Q000187:drug effects* / Q000378:metabolism / Q000502:physiology; D015513:Oncogene Proteins / Q000235:genetics / Q000502:physiology*; D011518:Proto-Oncogene Proteins; D019009:Proto-Oncogene Proteins c-kit / Q000378:metabolism / Q000502:physiology; D020794:Receptor Protein-Tyrosine Kinases / Q000235:genetics / Q000502:physiology*; D015398:Signal Transduction / Q000187:drug effects / Q000235:genetics / Q000502:physiology; D020825:T-Box Domain Proteins / Q000502:physiology; D000094963:Axl Receptor Tyrosine Kinase; D000098815:T-bet Transcription Factor; D000099255:Growth Arrest-Specific Protein 6
D018952:Antigens, CD34; D016207:Cytokines; D036341:Intercellular Signaling Peptides and Proteins; D019409:Interleukin-15; D015513:Oncogene Proteins; D011518:Proto-Oncogene Proteins; D019009:Proto-Oncogene Proteins c-kit; D020794:Receptor Protein-Tyrosine Kinases; D020825:T-Box Domain Proteins; D000094963:Axl Receptor Tyrosine Kinase; D000098815:T-bet Transcription Factor; D000099255:Growth Arrest-Specific Protein 6; C000722289:AXL protein, human