Ligand binding to inhibitory killer cell Ig-like receptors induce colocalization with Src homology domain 2-containing protein tyrosine phosphatase 1 and interruption of ongoing activation signals Journal Article


Authors: Vyas, Y. M.; Maniar, H.; Lyddane, C.; Sadelain, M.; Dupont, B.
Article Title: Ligand binding to inhibitory killer cell Ig-like receptors induce colocalization with Src homology domain 2-containing protein tyrosine phosphatase 1 and interruption of ongoing activation signals
Abstract: Interaction of NK cells with target cells leads to formation of an immunological synapse (IS) at the contact site. NK cells form two distinctly different IS, the inhibitory NK cell IS (NKIS) and the cytolytic NKIS. Cognate ligand binding is sufficient to induce clustering of inhibitory killer cell Ig-like receptors (KIR) and phosphorylation of both the receptor and the phosphatase Src homology domain 2-containing protein tyrosine phosphatase 1 (SHP-1). Recruitment and activation of SHP-1 by a signaling competent inhibitory receptor are essential early events for NK cell inhibition. We have in the present study used three-dimensional immunofluorescence microscopy to analyze distribution of inhibitory KIR, SHP-1, LFA-1, and lipid rafts within the NKIS during cytolytic and noncytolytic interactions. NK clones retrovirally transduced with the inhibitory KIR2DL3 gene fused to GFP demonstrate colocalization of KIR2DL3 with SHP-1 in the center of early inhibitory NKIS. Ligand binding translocates the receptor to the center of the IS where activation signals are accumulating and provides a docking site for SHP-1. SHP-1 and rafts cluster in the center of early inhibitory NKIS and late cytolytic NKIS, and whereas rafts continue to increase in size in cytolytic conjugates, they are rapidly dissolved in inhibitory conjugates. Furthermore, rafts are essential, only for cytolytic, not for inhibitory, outcome. These results indicate that the outcome of NK cell-target cell interactions is dictated by early quantitative differences in cumulative activating and inhibitory signals.
Keywords: controlled study; protein phosphorylation; unclassified drug; human cell; gene; green fluorescent protein; lipid; enzyme activation; phosphorylation; luminescent proteins; transduction, genetic; protein processing, post-translational; recombinant fusion proteins; imaging, three-dimensional; intracellular signaling peptides and proteins; gene fusion; ligands; natural killer cell; killer cells, natural; green fluorescent proteins; microscopy, fluorescence; killer cell immunoglobulin like receptor; target cell; cytotoxicity, immunologic; genes, reporter; cell clone; cell interaction; ligand binding; protein tyrosine phosphatase shp 1; protein tyrosine phosphatase shp 2; cytosol; gene location; immunofluorescence microscopy; lymphocyte function-associated antigen-1; receptors, immunologic; membrane microdomains; cell receptor; conjugate; protein-tyrosine-phosphatase; humans; human; priority journal; article; kir2dl3 gene; shp1 protein tyrosine phosphatase
Journal Title: Journal of Immunology
Volume: 173
Issue: 3
ISSN: 0022-1767
Publisher: The American Association of Immunologists, Inc  
Date Published: 2004-08-01
Start Page: 1571
End Page: 1578
Language: English
PROVIDER: scopus
PUBMED: 15265884
DOI: 10.4049/​jimmunol.173.3.1571
DOI/URL:
Notes: J. Immunol. -- Cited By (since 1996):24 -- Export Date: 16 June 2014 -- CODEN: JOIMA C2 - 15265884 -- Source: Scopus
Altmetric Score
MSK Authors
  1. Hina S Maniar
    8 Maniar
  2. Yatin M Vyas
    25 Vyas
  3. Michel W J Sadelain
    475 Sadelain
  4. Bo Dupont
    176 Dupont
  5. Clay   Lyddane
    10 Lyddane