Molecular Mechanism of the Activation-Induced Cell Death Inhibition Mediated by a p70 Inhibitory Killer Cell Ig-Like Receptor in Jurkat T Cells
Diglycerides/pharmacology
Cytoplasm
Apoptosis
Ligands
Lymphocyte Activation
Jurkat Cells
Apoptosis/genetics
Receptors
Membrane Proteins/immunology
Killer Cells
Isoenzymes/metabolism
Recombinant Proteins/pharmacology
Lymphocyte Activation*/drug effects
Protein Kinase C
0303 health sciences
Membrane Glycoproteins
Cytoplasm/immunology
Ionomycin
Isoenzymes/antagonists & inhibitors
Phytohemagglutinins/pharmacology
KIR
Isoenzymes
Killer Cells, Natural
Immunologic/biosynthesis
Cytoplasm/chemistry
Peptide Fragments/immunology
T-Lymphocytes/cytology
570
Fas Ligand Protein
Protein Kinase C-alpha
Protein Kinase C/antagonists & inhibitors
Molecular Sequence Data
Membrane Glycoproteins/antagonists & inhibitors
Protein Kinase C/metabolism
Phosphatidylserines
Diglycerides
Apoptosis/immunology*
03 medical and health sciences
T-Lymphocytes/drug effects
Cytoplasm/enzymology
KIR3DL1
Humans
Amino Acid Sequence
Membrane Proteins/genetics
Peptide Fragments/genetics
Phytohemagglutinins
Phosphatidylserines/pharmacology
Peptide Fragments/pharmacology
Membrane Proteins/pharmacology
Immunologic/genetics
Apoptosis/drug effects
Ionomycin/pharmacology
Membrane Proteins
Immunologic/physiology*
Cytoplasm/genetics
Natural/metabolism
Lymphocyte Activation*/genetics
Peptide Fragments
Natural/immunology
Protein Kinase C-theta
Membrane Glycoproteins/biosynthesis
DOI:
10.4049/jimmunol.169.7.3726
Publication Date:
2014-04-21T23:18:01Z
AUTHORS (7)
ABSTRACT
AbstractIn this study we investigated the molecular mechanism of the activation-induced cell death (AICD) inhibition mediated by a p70 inhibitory killer cell Ig-like receptor (KIR3DL1, also called NKB1) in Jurkat T cells. Using stable Jurkat transfectants that express KIR or CD8-KIR fusion proteins we have shown for the first time that KIR inhibits, in a ligation-independent manner, the AICD induced by PHA, PMA/ionomycin, or anti-CD3 Ab. The AICD inhibition mediated by KIR appears to result from the blockade of Fas ligand induction upon activation of the Jurkat transfectants. Moreover, the membrane-proximal 20 aa of the KIR cytoplasmic tail were determined to play a crucial role in this process. Since the membrane-proximal portion of the KIR cytoplasmic tail contains a putative protein kinase C (PKC) substrate site, we investigated the molecular interaction between KIR and PKC. Immunoprecipitation analysis demonstrated that KIR constitutively bound both to PKCα, a conventional Ca2+-dependent PKC, and to PKCθ, a novel Ca2+-independent PKC. Furthermore, an in vitro kinase assay revealed that PKC activation was blocked after PHA stimulation in Jurkat transfectants expressing KIR. These observations were supported by the finding that a recombinant KIR cytoplasmic tail also appeared to inhibit PKCα activation in vitro. Taken together these data strongly suggest that KIR inhibits the AICD of T cells by blocking Fas ligand induction upon stimulation, in a process that seems to be accomplished by PKC recruitment to the membrane-proximal PKC binding site and subsequent inhibition of PKC activation against the activating stimuli.
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CITATIONS (36)
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