SELECTIVE-INHIBITION OF HUMAN AND MOUSE NATURAL-KILLER TUMOR RECOGNITION USING RETROVIRAL ANTISENSE IN PRIMARY NATURAL-KILLER-CELLS - INVOLVEMENT WITH MHC CLASS-I KILLER-CELL INHIBITORY RECEPTORS

The natural killer tumor recognition (NK-TR) protein has been shown to be a necessary component for the killing of NK-sensitive and virus-in fected targets by the rat RNK-16 cell line. Class I-recognizing killer cell inhibitory receptors (KIR) have been found in the human (p58; NK AT family) and mouse (Ly-49 family). The principal functional characte ristic of these receptors is their ability to block NK cell lysis by r ecognition of selected class I molecules on target cells. In the prese nt study, we examined whether abrogation of NK-TR expression by retrov iral infection of primary human or mouse NK cells with virus-producing antisense NK-TR also would demonstrate loss of non-MHC-restricted kil ling and whether the NK-TR was associated with KIR function in humans or with Ly-49 in the mouse. Using short term culture of fresh human or mouse NK cells, antisense NK-TR-treated NK cells demonstrated strong selective reduction of NK cytotoxicity, NK-TR was necessary for lytic activity even when KIR function was blocked by Ab in experiments invol ving NK3.3 lysis of HLA.cw3-expressing targets or killing of D-d targe ts by Ly-49A(+) or Ly-49G2(+) mouse NK cells. These studies extend our previous studies in rat NK cell lines to demonstrate that primary mou se and human NK cells require NK-TR for non-MHC-restrided lysis of tum or and virus-infected targets. In addition, the reversal of KIR or Ly- 49 inhibition of NK cell lysis requires NK-TR expression for cellular killing in both human and mouse.