Axl/Gas6 pathway positively regulates FLT3 activation in human natural killer cell development

Eur J Immunol. 2013 Oct;43(10):2750-5. doi: 10.1002/eji.201243116. Epub 2013 Jul 8.

Abstract

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.

Keywords: Axl; CD34+ HPC; FMS-like tyrosine kinase 3 (FLT3); NK cell.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Antigens, CD34 / metabolism
  • Axl Receptor Tyrosine Kinase
  • Cell Differentiation / drug effects
  • Cell Differentiation / immunology
  • Cells, Cultured
  • Hematopoietic Stem Cells / drug effects
  • Hematopoietic Stem Cells / immunology*
  • Humans
  • Immunoglobulin Fc Fragments / genetics
  • Immunoglobulin Fc Fragments / immunology
  • Immunoglobulin Fc Fragments / metabolism*
  • Intercellular Signaling Peptides and Proteins / metabolism*
  • Interleukin Receptor Common gamma Subunit / genetics
  • Interleukin Receptor Common gamma Subunit / metabolism
  • Interleukin-15 / immunology
  • Interleukin-2 Receptor beta Subunit / genetics
  • Interleukin-2 Receptor beta Subunit / metabolism
  • Killer Cells, Natural / drug effects
  • Killer Cells, Natural / immunology*
  • Lymphocyte Activation / drug effects
  • Phosphorylation / drug effects
  • Protein Binding / drug effects
  • Proto-Oncogene Proteins / genetics
  • Proto-Oncogene Proteins / immunology
  • Proto-Oncogene Proteins / metabolism*
  • Receptor Protein-Tyrosine Kinases / genetics
  • Receptor Protein-Tyrosine Kinases / immunology
  • Receptor Protein-Tyrosine Kinases / metabolism*
  • Recombinant Fusion Proteins / genetics
  • Recombinant Fusion Proteins / immunology
  • Recombinant Fusion Proteins / metabolism*
  • Signal Transduction / drug effects
  • Signal Transduction / immunology
  • fms-Like Tyrosine Kinase 3 / metabolism*

Substances

  • Antigens, CD34
  • Immunoglobulin Fc Fragments
  • Intercellular Signaling Peptides and Proteins
  • Interleukin Receptor Common gamma Subunit
  • Interleukin-15
  • Interleukin-2 Receptor beta Subunit
  • Proto-Oncogene Proteins
  • Recombinant Fusion Proteins
  • growth arrest-specific protein 6
  • FLT3 protein, human
  • Receptor Protein-Tyrosine Kinases
  • fms-Like Tyrosine Kinase 3
  • Axl Receptor Tyrosine Kinase
  • AXL protein, human