Genome-wide siRNA screen reveals a new cellular partner of NK cell receptor KIR2DL4: Heparan sulfate directly modulates KIR2DL4-mediated responses

Michael Brusilovsky, Moti Cordoba, Benyamin Rosental, Oren Hershkovitz, Mark D. Andrake, Anna Pecherskaya, Margret B. Einarson, Yan Zhou, Alex Braiman, Kerry S. Campbell, Angel Porgador

Research output: Contribution to journalArticlepeer-review

35 Scopus citations

Abstract

KIR2DL4 (CD158d) is a distinct member of the killer cell Ig-like receptor (KIR) family in human NK cells that can induce cytokine production and cytolytic activity in resting NK cells. Soluble HLA-G, normally expressed only by fetal-derived trophoblast cells, was reported to be a ligand for KIR2DL4; however, KIR2DL4 expression is not restricted to the placenta and can be found in CD56high subset of peripheral blood NK cells. We demonstrated that KIR2DL4 can interact with alternative ligand(s), expressed by cells of epithelial or fibroblast origin. A genome-wide high-throughput siRNA screen revealed that KIR2DL4 recognition of cell-surface ligand(s) is directly regulated by heparan sulfate (HS) glucosamine 3-O-sulfotransferase 3B1 (HS3ST3B1). KIR2DL4 was found to directly interact with HS/heparin, and the D0 domain of KIR2DL4 was essential for this interaction. Accordingly, exogenous HS/heparin can regulate cytokine production by KIR2DL4-expressing NK cells and HEK293T cells (HEK293T-2DL4), and induces differential localization of KIR2DL4 to rab5+ and rab7+ endosomes, thus leading to downregulation of cytokine production and degradation of the receptor. Furthermore, we showed that intimate interaction of syndecan-4 (SDC4) HS proteoglycan (HSPG) and KIR2DL4 directly affects receptor endocytosis and membrane trafficking.

Original languageEnglish
Pages (from-to)5256-5267
Number of pages12
JournalJournal of Immunology
Volume191
Issue number10
DOIs
StatePublished - 15 Nov 2013

ASJC Scopus subject areas

  • Immunology and Allergy
  • Immunology

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