CD33 (Siglec-3) Inhibitory Function: Role in the NKG2D/DAP10 Activating Pathway

J Immunol Res. 2019 Apr 15;2019:6032141. doi: 10.1155/2019/6032141. eCollection 2019.


CD33 (siglec-3), a well-known target in leukemia therapy, is an inhibitory sialoadhesin expressed in human leukocytes of the myeloid lineage and some lymphoid subsets, including NK cells. It may constitute a control mechanism of the innate immune system; nevertheless, its role as an inhibitory receptor remains elusive. Using human NK cells as a cellular model, we analyzed CD33 inhibitory function upon different activating receptors. In high-cytotoxicity NKL cells, CD33 displayed a prominent inhibition on cytotoxicity triggered by the activating receptors NKG2D and, in a lower extent, 2B4, whereas it did not inhibit NKp46-induced cytotoxicity. NKp46 was partially inhibited by CD33 only when low-cytotoxicity NKL cells were tested. CD33 triggering did not inhibit IFN-γ secretion, contrasting with ILT-2 and CD94/NKG2A inhibitory receptors that inhibited cytotoxicity and IFN-γ secretion induced by all activating receptors tested. CD33-mediated inhibition of NKG2D-induced triggering involved Vav1 dephosphorylation. Our results support the role of CD33 as an inhibitory receptor preferentially regulating the NKG2D/DAP10 cytotoxic signaling pathway, which could be involved in self-tolerance and tumor and infected cell recognition.

MeSH terms

  • Cytotoxicity, Immunologic
  • Humans
  • Infections / immunology*
  • K562 Cells
  • Killer Cells, Natural / immunology*
  • NK Cell Lectin-Like Receptor Subfamily C / metabolism
  • NK Cell Lectin-Like Receptor Subfamily K / metabolism*
  • Natural Cytotoxicity Triggering Receptor 1 / metabolism
  • Neoplasms / immunology*
  • Phosphorylation
  • Proto-Oncogene Proteins c-vav / metabolism
  • Receptors, Immunologic / metabolism
  • Self Tolerance
  • Sialic Acid Binding Ig-like Lectin 3 / metabolism*
  • Signal Transduction


  • HCST protein, human
  • KLRK1 protein, human
  • NCR1 protein, human
  • NK Cell Lectin-Like Receptor Subfamily C
  • NK Cell Lectin-Like Receptor Subfamily K
  • Natural Cytotoxicity Triggering Receptor 1
  • Proto-Oncogene Proteins c-vav
  • Receptors, Immunologic
  • Sialic Acid Binding Ig-like Lectin 3
  • VAV1 protein, human