ORIGIN AND FUNCTIONS OF HUMAN NATURAL-KILLER-CELLS

Recent data have substantially modified our view of natural killer cel ls. Although maturation of natural killer cells occurs in the absence of a functional thymus, we have shown that clonogenic precursors capab le of differentiating into mature CD3-16+56+ natural killer cells exis t in CD3-4-8-16- populations isolated from human thymus. Analysis of p eripheral blood-derived natural killer clones showed that they can lys e normal cells (e.g., phytohemagglutinin-induced blasts) isolated from some individuals. Importantly, natural killer clones isolated from si ngle individuals displayed different patterns of cytolytic activity ag ainst a panel of normal allogeneic cells. These data suggested the exi stence of a natural killer cell repertoire. A number of observations h ave revealed that the expression of given HLA class I alleles protects target cells from lysis by different groups of natural killer clones. Evidence has been gained by genetic analysis of the determinants resp onsible for susceptibility/resistance to lysis by natural killer clone s together with analysis, as target cells, of HLA-defective variants o r HLA transfectants. Thus, natural killer cells were found to express a clonally distributed ability to recognize HLA class I alleles. The s election of new monoclonal antibodies directed against members of a no vel family of natural killer specific p58 molecules allowed the identi fication of the putative natural killer receptors for different MHC cl ass I alleles. Firstly, a correlation was established between the expr ession of given p58 molecules (e.g., EB6 and GL183) and the class I al leles recognized. Secondly, anti-p58 monoclonal antibodies restored th e natural killer-mediated lysis of class I-protected cells. A similar effect was obtained by inducing modulation of p58 surface molecules wi th anti-p58 monoclonal antibodies. The implications of these receptor/ ligand interactions in the physiopathological behavior of natural kill er cells are discussed.