Regulation of natural cytotoxicity receptors by heparan sulfate proteoglycans in -cis: A lesson from NKp44

Eur J Immunol. 2015 Apr;45(4):1180-91. doi: 10.1002/eji.201445177. Epub 2015 Jan 21.


NKp44 (NCR2) is a distinct member of natural cytotoxicity receptors (NCRs) family that can induce cytokine production and cytolytic activity in human NK cells. Heparan sulfate proteoglycans (HSPGs) are differentially expressed in various normal and cancerous tissues. HSPGs were reported to serve as ligands/co-ligands for NKp44 and other NCRs. However, HSPG expression is not restricted to either group and can be found also in NK cells. Our current study reveals that NKp44 function can be modulated through interactions with HSPGs on NK cells themselves in -cis rather than on target cells in -trans. The intimate interaction of NKp44 and the NK cell-associated HSPG syndecan-4 (SDC4) in -cis can directly regulate membrane distribution of NKp44 and constitutively dampens the triggering of the receptor. We further demonstrate, that the disruption of NKp44 and SDC4 interaction releases the receptor to engage with its ligands in -trans and therefore enhances NKp44 activation potential and NK cell functional response.

Keywords: Heparan sulfate; Heparan sulfate proteoglycans; Immune regulation; NCR2; NK cell activation; NKp44; Natural cytotoxicity receptors; Syndecan 4.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Binding Sites / genetics
  • Binding Sites / immunology
  • Cell Line, Tumor
  • Cytokines / biosynthesis
  • Heparan Sulfate Proteoglycans / metabolism*
  • Humans
  • Killer Cells, Natural / immunology*
  • Natural Cytotoxicity Triggering Receptor 2 / metabolism*
  • Neoplasms / immunology
  • Protein Binding / immunology
  • Receptors, Immunologic / immunology
  • Syndecan-4 / metabolism*


  • Cytokines
  • Heparan Sulfate Proteoglycans
  • NCR2 protein, human
  • Natural Cytotoxicity Triggering Receptor 2
  • Receptors, Immunologic
  • SDC4 protein, human
  • Syndecan-4