Natural killer (NK) cells are nonimmune cytotoxic effector cells that have the capacity to lyse certain types of NK-sensitive tumor cells. NK cells are thought to participate in immune surveillance. Therefore, elucidating the NK lytic mechanism, as well as the mechanism whereby some tumor cells resist lysis by NK cells, may provide new ideas that can be applied to cancer therapy. Evidence indicates NK target cell lysis is mediated by natural killer cytotoxic factors (NKCF) released from the NK cell following contact with the target cell. Studies using NK-resistant variants derived from the initially NK-sensitive YAC-1 cell line have indicated there are at least four characteristics that determine NK sensitivity in a tumor cell. Those are: (1) expression of the NK target structure; (2) ability to stimulate release of NKCF; (3) membrane receptors for NKCF; and (4) sensitivity to lysis by NKCF. Based on these studies, we intend to analyze the role of NKCF receptors in the murine NK lytic mechanism using the NK-sensitive YAC-1 tumor cell as well as NK-resistant variants derived from YAC-1. Two of these variants (YAC-R15.1 and YAC-6-28) do not express NKCF receptors, whereas YAC-asc cells do express the receptor, although they are resistant to lysis. Monoclonal antibodies will be generated against the NKCF receptor and will be used to study the function of YAC-1 NKCF receptors as well as those expressed by the NK-resistant variants. Fluorescinated antibodies will be used to study the expression of NKCF receptors and to determine if the receptor may undergo endocytosis. Other studies will examine the morphological alterations both YAC-1 cells and the resistant variants undergo after exposure to NKCF. The effects of metabolic inhibitors will be tested to determine if NK-resistant variants engage in repair processes to counteract lysis by NKCF. Finally, techniques will be developed for the isolation and purification of NKCF receptors using the monoclonal antibodies in combination with conventional biochemical techniques. These studies will help to elucidate the NK lytic mechanism at the level of the NKCF-receptor interaction as well as to analyze mechanisms whereby tumor cells may resist lysis by NK cells. (CS)
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