Interferon-gamma-induced membrane PAF-receptor expression confers tumor cell susceptibility to NK perforin-dependent lysis.
Perforin is known to display a membranolytic activity on tumor cells. Nevertheless, perforin release during natural killer (NK)-cell activation is not sufficient to induce membrane target-cell damage. On the basis of the ability of perforin to interact with phospholipids containing a choline phosphate headgroup, we identify the platelet-activating factor (PAF) and its membrane receptor as crucial components in tumor cell killing activity of human resting NK cells. We demonstrate for the first time that upon activation, naive NK cells release the choline phosphate-containing lysolipid PAF, which binds to perforin and acts as an agonist on perforin-induced membrane damage. PAF is known to incorporate cell membranes using a specific receptor. Here we show that interferon-gamma (IFN-gamma) secreted from activated NK cells ends in PAF-receptor expression on perforin-sensitive K562 cells but not on perforin-resistant Daudi cells. In order to prove the capacity of PAF to interact simultaneously with its membrane PAF receptor and with perforin, we successfully co-purified the 3 components in the presence of bridging PAF molecules. The functional activity of this complex was further examined. The aim was to determine whether membrane PAF-receptor expression on tumor cells, driven to express this receptor, could render them sensitive to the perforin lytic pathway. The results confirmed that transfection of the PAF-receptor complementary DNA into major histocompatibility complex class I and Fas-receptor negative tumor cells restored susceptibility to naive NK cells and perforin attack. Failure of IFN-gamma to induce membrane PAF receptor constitutes the first described mechanism for tumor cells to resist the perforin lytic pathway.
Berthou
C
C
INSERM U462, Hôpital St Louis, Paris, France.
Bourge
J F
JF
Zhang
Y
Y
Soulié
A
A
Geromin
D
D
Denizot
Y
Y
Sigaux
F
F
Sasportes
M
M
D000328:Adult; D001381:Azepines / Q000494:pharmacology; D002118:Calcium / Q000494:pharmacology; D002462:Cell Membrane / Q000378:metabolism*; D003602:Cytotoxicity, Immunologic; D015870:Gene Expression; D006801:Humans; D007371:Interferon-gamma / Q000494:pharmacology*; D007694:Killer Cells, Natural / Q000276:immunology*; D008562:Membrane Glycoproteins / Q000378:metabolism / Q000494:pharmacology*; D009369:Neoplasms / Q000276:immunology*; D054353:Perforin; D010972:Platelet Activating Factor / Q000378:metabolism / Q000494:pharmacology; D010975:Platelet Aggregation Inhibitors / Q000494:pharmacology; D010980:Platelet Membrane Glycoproteins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D052899:Pore Forming Cytotoxic Proteins; D011956:Receptors, Cell Surface; D043562:Receptors, G-Protein-Coupled; D013844:Thiazoles / Q000494:pharmacology; D014162:Transfection; D014230:Triazoles / Q000494:pharmacology; D014407:Tumor Cells, Cultured
D001381:Azepines; D008562:Membrane Glycoproteins; D010972:Platelet Activating Factor; D010975:Platelet Aggregation Inhibitors; D010980:Platelet Membrane Glycoproteins; D052899:Pore Forming Cytotoxic Proteins; D011956:Receptors, Cell Surface; D043562:Receptors, G-Protein-Coupled; D013844:Thiazoles; D014230:Triazoles; C039351:platelet activating factor receptor; C052518:WEB 2086; D054353:Perforin; D007371:Interferon-gamma; D002118:Calcium; C071317:Foropafant