Inhibition of natural killer cytotoxicity by extracellular ppp(A2'p5')nA oligonucleotides

The effect of purified 2'-5' linked polyadenylated oligomers on the human natural killer (NK) activity has been investigated. Permeabilization of NK cells to ppp(A2'p5')2A did not enhance their NK activity at any concentration tested. Furthermore, concentrations higher than 0.1 mM inhibited their NK activity. Similar results were obtained by pre-incubating non-permeabilized intact cells, indicating an extracellular effect of these compounds on cell membranes, which was further investigated. This inhibition by the oligomers was greater (50% inhibition was obtained with 50 micron), when they were added directly to the NK assay, than when the NK cells were pre-incubated. Similar inhibitory effects were observed with ppp(A2'p5')A and ppp(A2'p5')3A oligomers but not with the dephosphorylated "core" molecules or other nucleotides. The inhibition was completely or partially reversed by phorbol esters and by interferon (IFN), respectively. The inhibition was temperature and extracellular Ca2+ dependent. The oligomers did not inhibit the binding of the effector cells to the target cells. The programming for lysis was the step of the lytic mechanism affected, possibly due to the alteration of the Ca2+ influx into the NK cells observed in presence of the ppp(A2'p5')nA.