Neutrophil activation and survival are modulated by interaction with NK cells

Int Immunol. 2010 Oct;22(10):827-38. doi: 10.1093/intimm/dxq434. Epub 2010 Aug 25.


It is increasingly evident that neutrophils are able to cross-talk with other leukocytes to shape ongoing inflammatory and immune responses. In this study, we analyzed whether human NK cells may influence the survival and activation of neutrophils under co-culture conditions. We report that NK cells exposed to either IL-15 or IL-18 alone strongly protect the survival of neutrophils via the release of IFNγ and granulocyte macrophage colony-stimulating factor (GM-CSF) plus IFNγ, respectively, and cause a slight up-regulation of neutrophil CD64 and CD11b expression. In comparison, NK cells exposed to both IL-15 and IL-18 show a lesser ability to increase the survival of neutrophils but can more potently up-regulate CD64 and CD11b expression, as well as induce the de novo surface expression of CD69, in neutrophils. Analysis of the events occurring in neutrophil/NK co-cultures exposed to IL-15 plus IL-18 revealed that (i) neutrophil survival is positively affected by NK-derived GM-CSF but negatively influenced by a CD18-dependent neutrophil/NK contact, (ii) NK-derived IFNγ is almost entirely responsible for the induction of CD64, (iii) both soluble factors (primarily GM-CSF) and direct cell-cell contact up-regulate CD11b and CD69 and (iv) NK-derived GM-CSF induces the expression of biologically active heparin-binding EGF-like growth factor (HB-EGF) in neutrophils. Finally, we demonstrate that NK cells can also express HB-EGF when stimulated with either IL-2 or IL-15, yet independently of endogenous GM-CSF. Altogether, our results define a novel interaction within the innate immune system whereby NK cells, by directly modulating neutrophil functions, might contribute to the pathogenesis of inflammatory diseases.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Apoptosis
  • Cell Communication / immunology*
  • Cell Survival
  • Cells, Cultured
  • Coculture Techniques
  • Cytokines / genetics
  • Cytokines / metabolism*
  • Cytokines / pharmacology
  • Gene Expression Regulation*
  • Heparin-binding EGF-like Growth Factor
  • Humans
  • Inflammation / immunology
  • Inflammation / physiopathology*
  • Intercellular Signaling Peptides and Proteins / genetics
  • Intercellular Signaling Peptides and Proteins / metabolism
  • Killer Cells, Natural / drug effects
  • Killer Cells, Natural / immunology*
  • Killer Cells, Natural / metabolism
  • Neutrophil Activation / immunology*
  • Neutrophils / drug effects
  • Neutrophils / immunology
  • Neutrophils / metabolism
  • Neutrophils / physiology*


  • Cytokines
  • HBEGF protein, human
  • Heparin-binding EGF-like Growth Factor
  • Intercellular Signaling Peptides and Proteins