SELECTIVE LOSS OF NK CYTOTOXICITY IN ANTISENSE NK-TR1 RAT LGL CELL-LINES - ABROGATION OF ANTIBODY-INDEPENDENT TUMOR AND VIRUS-INFECTED TARGET-CELL KILLING

We have shown that NK-TR1, a protein containing a cyclophilin-like dom ain, is associated with a receptor/ triggering molecule on the surface of human large granular lymphocytes (1). In the present study, we hav e further defined the role of NK-TR1 in target cell recognition/killin g by generating antisense NK-TR1 transfectants in the rat LGL cell lin e, RNK-16. Stable transfectants were identified by analyzing permeabil ized cells with the anti-NK-TR1 mAb, 4F9. Transfectants with low level s of 4F9 staining showed drastically reduced levels of killing against three NK-susceptible target cell lines. Lytic activity against vaccin ia virus-infected cell lines also was dramatically reduced. In contras t, transfected cells showing normal levels of NK-TR1 expression demons trated normal killing of all target cells. The ability of all transfec tants to form conjugates was identical to that observed with the wild- type RNK cell line. Lectin-dependent cytotoxicity, reverse ADCC via NK R-PI, and ADCC-mediated killing were comparable in both high or low NK -TR1 expressing clones, demonstrating that the lytic machinery was sti ll intact. BLT-esterase activity, PF levels, and surface marker phenot ype were not significantly affected. These results provide strong evid ence that NK-TR1 is an essential element in a signaling pathway leadin g to MHC unrestricted killing of tumor and virus-infected cells.