KIR2DL4 differentially signals downstream functions in human NK cells through distinct structural modules

S. M.Shahjahan Miah, Tracey L. Hughes, Kerry S. Campbell

Research output: Contribution to journalArticlepeer-review

33 Scopus citations

Abstract

KIR2DL4 (2DL4) is a member of the killer cell Ig-like receptor (KIR) family in human NK cells. It can stimulate potent cytokine production and weak cytolytic activity in resting NK cells, but the mechanism for 2DL4-mediated signaling remains unclear. In this study we characterized the signaling pathways stimulated by 2DL4 engagement. In a human NK-like cell line, KHYG-1, cross-linking of 2DL4 activated MAPKs including JNK, ERK, and p38. Furthermore, 2DL4 cross-linking resulted in phosphorylation of IκB kinase β (IKKβ) and the phosphorylation and degradation of IκBα, which indicate activation of the classical NF-κB pathway. Engagement of 2DL4 was also shown to activate the transcription and translation of a variety of cytokine genes, including TNF-α, IFN-γ, MIP1α, MIP1β, and IL-8. Pharmacological inhibitors of JNK, MEK1/2 and p38, blocked IFN-γ, IL-8, and MIP1α production, suggesting that MAPKs are regulating 2DL4-mediated cytokine production in a nonredundant manner. Activation of both p38 and ERK appear to be upstream of the stimulation of NF-κB. Mutation of a transmembrane arginine in 2DL4 to glycine (R/G mutant) abrogated FcεRI-γ association, as well as receptor-mediated cytolytic activity and calcium responses. Surprisingly, the R/G mutant still activated MAPKs and the NF-κB pathway and selectively stimulated the production of MIP1α, but not that of IFN-γ or IL-8. In conclusion, we provide evidence that the activating functions of 2DL4 can be compartmentalized into two distinct structural modules: 1) through transmembrane association with FcεRI-γ; and 2) through another receptor domain independent of the transmembrane arginine.

Original languageEnglish
Pages (from-to)2922-2932
Number of pages11
JournalJournal of Immunology
Volume180
Issue number5
DOIs
StatePublished - Mar 1 2008

Keywords

  • Amino Acid Sequence
  • Amino Acid Substitution/genetics
  • Animals
  • Arginine/genetics
  • Cell Line, Tumor
  • Extracellular Signal-Regulated MAP Kinases/antagonists & inhibitors
  • Humans
  • Killer Cells, Natural/enzymology
  • MAP Kinase Signaling System/genetics
  • Mice
  • Mice, Inbred DBA
  • Molecular Sequence Data
  • NF-kappa B/metabolism
  • Protein Structure, Tertiary/genetics
  • Receptors, IgE/genetics
  • Receptors, KIR2DL4/chemistry
  • Signal Transduction/genetics

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