Abstract
Activating and inhibitory receptors control natural killer (NK) cell activity. T-cell immunoglobulin and ITIM (immunoreceptor tyrosine-based inhibition motif) domain (TIGIT) was recently identified as a new inhibitory receptor on T and NK cells that suppressed their effector functions. TIGIT harbors the immunoreceptor tail tyrosine (ITT)-like and ITIM motifs in its cytoplasmic tail. However, how its ITT-like motif functions in TIGIT-mediated negative signaling is still unclear. Here, we show that TIGIT/PVR (poliovirus receptor) engagement disrupts granule polarization leading to loss of killing activity of NK cells. The ITT-like motif of TIGIT has a major role in its negative signaling. After TIGIT/PVR ligation, the ITT-like motif is phosphorylated at Tyr225 and binds to cytosolic adapter Grb2, which can recruit SHIP1 to prematurely terminate phosphatidylinositol 3-kinase (PI3K) and MAPK signaling, leading to downregulation of NK cell function. In support of this, Tyr225 or Asn227 mutation leads to restoration of TIGIT/PVR-mediated cytotoxicity, and SHIP1 silencing can dramatically abolish TIGIT/PVR-mediated killing inhibition.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Amino Acid Motifs
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Cell Line
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GRB2 Adaptor Protein / antagonists & inhibitors
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GRB2 Adaptor Protein / genetics
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GRB2 Adaptor Protein / metabolism*
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Humans
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Inositol Polyphosphate 5-Phosphatases
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Killer Cells, Natural / immunology*
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Mitogen-Activated Protein Kinase Kinases / metabolism
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Mutation
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Phosphatidylinositol 3-Kinases / metabolism
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Phosphatidylinositol-3,4,5-Trisphosphate 5-Phosphatases
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Phosphoric Monoester Hydrolases / antagonists & inhibitors
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Phosphoric Monoester Hydrolases / genetics
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Phosphoric Monoester Hydrolases / metabolism*
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Phosphorylation
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RNA Interference
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RNA, Small Interfering / metabolism
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Receptors, Immunologic / chemistry
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Receptors, Immunologic / genetics
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Receptors, Immunologic / metabolism*
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Receptors, Virus / metabolism
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Signal Transduction
Substances
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GRB2 Adaptor Protein
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RNA, Small Interfering
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Receptors, Immunologic
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Receptors, Virus
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TIGIT protein, human
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poliovirus receptor
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Phosphatidylinositol 3-Kinases
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Mitogen-Activated Protein Kinase Kinases
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Phosphoric Monoester Hydrolases
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Inositol Polyphosphate 5-Phosphatases
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INPP5D protein, human
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INPPL1 protein, human
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Phosphatidylinositol-3,4,5-Trisphosphate 5-Phosphatases