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Summary: Human NK cells express clonally distributed receptors specific for HLA-A, -B and -C molecules. These receptors belong to the immunoglobulin superfamily and can be functionally distinguished as inhibitory or stimulatory Inhibitory receptors block NK-cell-mediated cytotoxicity upon binding to HLA class I ligands. This function is mediated by phosphorylation of cytoplasmic tyrosines, which recruit the protein tyrosine phosphatase SHP-1. Stimulatory receptors also bind HLA class I, lack cytoplasmic tyrosine-based motifs, and trigger NK cytotoxicity and proliferation. Both types of receptor are characterized by a limited diversity allowing for recognition of distinct class I supertypic epitopes. This limited diversity is counterbalanced by the expression of different combinations ill inhibitory and stimulatory receptors with self and/or non-self HLA class I specificities on distinct NK cell clones. This peculiar strategy allows NK cells to detect loss of MHC class I molecules on autologous transformed and virally infected cells with maximal sensitivity.