Recent studies on human NK cells have identified a number of surface antigens that can be utilized to define this population of cells and to identify functionally distinct subsets within this heterogeneous population. In addition, it has been possible to associate specific functional activities with several antigens expressed on NK cells as well as other hematopoietic cells. This information, which is summarized in Table III can be utilized to develop a framework for the classification of cytolytic effector cells. Of primary importance, this classification identifies subsets of cytolytic cells with distinct functional repertoires and distinct cytolytic mechanisms. The majority of NK cells in unstimulated peripheral blood and the majority of NK clones express NKH1 and CD2 antigens but do not express CD3 antigen. These cells morphologically appear as large granular lymphocytes and have broad cytolytic activity against a variety of allogeneic targets without primary sensitization. Consistent with the finding that these cells are CD3 negative, they have not been found to have rearrangement of genes encoding for TCR, or functional mRNA transcripts of either TCR alpha, TCR beta, or TCR gamma genes. In addition, these cells do not express heterodimeric surface proteins similar to those that have now been demonstrated to be MHC-restricted T cell receptors for antigen. Taken together, these findings provide strong evidence that NKH1+CD3- NK clones do not interact with target cells through a T cell receptor-like structure. Nevertheless, these NK cells do share several properties with conventional CTL. These functional T cell characteristics include (1) expression of CD2-T11/E rosette receptor antigen, and (2) utilization of LFA-1 surface antigen to enhance effector cell adhesion to target cells. As previously demonstrated for T cells, NK cells can be activated through the CD2 molecule and this has recently been shown to result in the enhancement of cytolytic function by these effectors. Since CD2 can also function as a cell surface ligand for LFA-3, an antigen expressed on NK targets, the CD2 molecule may be considered as a potential NK receptor structure. The fact that a very small subset of NK cells (approximately equal to 10%) as well as some NK clones (JT11) does not express CD2 argues against a potential role for CD2 as the NK cell receptor. Certainly, further studies will be necessary to clarify the role of CD2 on NK cells and to identify the mechanisms whereby NKH1+CD3- NK cells interact with targets in a non-MHC-restricted fashion.(ABSTRACT TRUNCATED AT 400 WORDS)