Natural killer (NK) cells are heterogeneous in their specificity and expression of cell surface molecules. In the mouse, the Ly-49A molecule is a primary determinant of NK cell specificity because of its ability to downregulate NK cell activation after physical interaction with target cell MHC class I molecules. Ly-49A is expressed on an NK cell subset, and it belongs to a family of highly related molecules that may similarly dictate major histocompatibility complex (MHC) class I-associated specificity of Ly-49A- NK cells. It is not known, however, whether murine NK cell specificity may occur independently of the Ly-49 family and target cell MHC class I molecules. Similar to the impact of cloned murine T cell lines on molecular description of T cell recognition, derivation of cloned murine NK cells should permit dissection of NK cell specificity but, to date, it has not been possible to produce such effector cells. In this study, we derived NK cell clones from mice that were homozygous for a mutation in the p53 tumor suppressor gene. The cloned cells displayed the molecular, cell surface, and functional phenotype of NK cells. Significantly, the NK cell clones displayed clonal differences in ability to kill a panel of murine tumor targets and did not lyse normal cells. Target lysis was unaffected by target cell MHC class I expression, and none of the clones expressed Ly-49A on the cell surface or transcripts for Ly-49 isoforms. Although consistent with the possibility that NK cell specificity for MHC class I molecules is mediated by the Ly-49 family of molecules, the results indicate that NK cell specificity also is regulated by a mechanism independent of target cell MHC class I and the Ly-49 family.

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