Abstract
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.
Publication types
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Research Support, N.I.H., Extramural
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Research Support, Non-U.S. Gov't
MeSH terms
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Antigens, CD34 / metabolism
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Antigens, CD34 / physiology
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Axl Receptor Tyrosine Kinase
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Cell Differentiation / drug effects*
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Cell Differentiation / genetics
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Cells, Cultured
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Cytokines / pharmacology
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Cytokines / physiology
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Hematopoietic Stem Cells / drug effects
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Hematopoietic Stem Cells / metabolism
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Hematopoietic Stem Cells / physiology
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Humans
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Intercellular Signaling Peptides and Proteins / genetics
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Intercellular Signaling Peptides and Proteins / physiology*
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Interleukin-15 / pharmacology*
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Interleukin-15 / physiology
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K562 Cells
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Killer Cells, Natural / drug effects*
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Killer Cells, Natural / metabolism
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Killer Cells, Natural / physiology
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Oncogene Proteins / genetics
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Oncogene Proteins / physiology*
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Proto-Oncogene Proteins
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Proto-Oncogene Proteins c-kit / metabolism
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Proto-Oncogene Proteins c-kit / physiology
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Receptor Protein-Tyrosine Kinases / genetics
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Receptor Protein-Tyrosine Kinases / physiology*
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Signal Transduction / drug effects
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Signal Transduction / genetics
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Signal Transduction / physiology
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T-Box Domain Proteins / physiology
Substances
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Antigens, CD34
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Cytokines
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Intercellular Signaling Peptides and Proteins
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Interleukin-15
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Oncogene Proteins
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Proto-Oncogene Proteins
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T-Box Domain Proteins
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T-box transcription factor TBX21
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growth arrest-specific protein 6
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Proto-Oncogene Proteins c-kit
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Receptor Protein-Tyrosine Kinases
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Axl Receptor Tyrosine Kinase
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AXL protein, human