Several of the generally accepted ideas on natural killer (NK) cells have been challenged by recent data that have substantially modified our view on these lymphoid cell populations. Although maturation of NK cells can occur in the absence of a functional thymus, clonogenic precursors capable of differentiating into mature CD3-16+56+ NK cells were found in CD3-4-8-16- populations isolated from human postnatal thymus. Analysis of the cytolytic activity of interleukin-2-activated NK cell populations and clones revealed that they can lyse normal cells (e.g., PHA blasts) isolated from certain individuals. In addition, NK clones isolated from single donors displayed different patterns of cytolytic activity against a panel of allogeneic cells, thus indicating that an NK cell repertoire exists. Genetic analyses of the determinants responsible for susceptibility/resistance to lysis together with the use of HLA-defective variants or HLA-transfectants revealed that the expression of given HLA class I alleles protects target cells from lysis by different groups of NK clones. Thus, NK cells express a clonally distributed ability to recognize HLA class I alleles. New monoclonal antibodies directed to members of a novel family of NK-specific p58 molecules allowed identification of the putative NK receptors for different major histocompatibility complex class I alleles. Indeed, a precise correlation has been established between expression of given p58 molecules (e.g., EB6 and GL183 molecules) and class I alleles recognized. In addition, anti-p58 monoclonal antibodies restored the NK-mediated lysis of class I-protected cells.(ABSTRACT TRUNCATED AT 250 WORDS)