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Negative regulation of t cell receptor signaling by siglec-7 (p70/airm) and siglec-9

Academic Article
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Overview

authors

  • Ikehara, Y.
  • Ikehara, S. K.
  • Paulson, James

publication date

  • 2004

journal

  • Journal of Biological Chemistry  Journal

abstract

  • Siglec-7 (p70/AIRM) and Siglec-9 are "CD33"-related siglecs expressed on natural killer (NK) cells and subsets of peripheral T cells. Like other inhibitory NK cell receptors, they contain immunoglobulin receptor family tyrosine-based inhibitory motifs in their cytoplasmic domains, and Siglec-7 has been demonstrated to negatively regulate NK cell activation. Based on reports of the presence of these siglecs on T cells, we sought to determine if they are capable of modulating T cell receptor (TCR) signaling using Jurkat T cells stably and transiently transfected with Siglec-7 or Siglec-9. Following either pervanadate stimulation or TCR engagement, both Siglecs exhibited increased tyrosine phosphorylation and recruitment of SHP-1. Effects of Siglec-7 and -9 were also evident in downstream events in the signaling pathway. Both siglecs reduced phosphorylation of Tyr319 on ZAP-70, known to play a pivotal role in up-regulation of gene transcription following TCR stimulation. There was also a corresponding decreased transcriptional activity of nuclear factor of activated T cells (NFAT) as determined using a luciferase reporter gene. Like all siglecs, Siglec-7 and -9 recognize sialic acid-containing glycans of glycoproteins and glycolipids as ligands. Mutation of the conserved Arg in the ligand binding site of Siglec-7 (Arg124) or Siglec-9 (Arg120) resulted in reduced inhibitory function in the NFAT/luciferase transcription assay, suggesting that ligand binding is required for optimal inhibition of TCR signaling. The combined results demonstrate that both Siglec-7 and Siglec-9 are capable of negative regulation of TCR signaling and that ligand binding is required for optimal activity.

subject areas

  • Amino Acid Motifs
  • Antigens, CD
  • Antigens, Differentiation, Myelomonocytic
  • Blotting, Western
  • Cell Separation
  • Cytoplasm
  • Dose-Response Relationship, Drug
  • Enzyme Activation
  • Enzyme Inhibitors
  • Flow Cytometry
  • Genes, Reporter
  • Humans
  • Immunoprecipitation
  • Jurkat Cells
  • Lectins
  • Ligands
  • Luciferases
  • Microscopy, Fluorescence
  • Models, Biological
  • Phosphorylation
  • Protein Binding
  • Protein Structure, Tertiary
  • Protein-Tyrosine Kinases
  • Sialic Acid Binding Ig-like Lectin 3
  • Sialic Acid Binding Immunoglobulin-like Lectins
  • Signal Transduction
  • T-Lymphocytes
  • Time Factors
  • Transcription, Genetic
  • Transcriptional Activation
  • Transfection
  • Tyrosine
  • Vanadates
  • ZAP-70 Protein-Tyrosine Kinase
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Identity

International Standard Serial Number (ISSN)

  • 0021-9258

Digital Object Identifier (DOI)

  • 10.1074/jbc.M403538200

PubMed ID

  • 15292262
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Additional Document Info

start page

  • 43117

end page

  • 43125

volume

  • 279

issue

  • 41

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