NK cell triggering by the human costimulatory molecules CD80 and CD86

NK cell-mediated effector functions are regulated by a delicate balance bet ween positive and negative signals. Receptors transmitting negative signals upon engagement with target cell MHC class I molecules have been character ized in detail in recent years. In contrast, less information is available about receptor-ligand interactions involved in the transmission of positive or "triggering" signals to NK cells. Recently, it has been described that murine NK cells are triggered by the costimulatory molecules CD80, CD86, an d CD40. Using NK cell lines derived from PBMC as effecters, we demonstrate that the human CD80 and CD86 gene products can function as triggering molec ules for NK cell-mediated cytotoxicity. Expression of human CD80 or CD86 mo lecules in murine B16.F1 melanoma cells rendered these significantly more s usceptible to lysis by human NK cell lines. Blocking of the transfected gen e products with specific mAb reduced lysis levels to that of nontransfected control cell lines. Triggering of human Mt cells by CD80 and CD86 appeared to be independent of CD28 and CTLA-4 at least as determined by the reagent s used in the present study, because the expression of these molecules coul d not be detected on the NK cell lines by either flow cytometry or in redir ected lysis assays. Thus, human NR cells may use receptors other than CD28 and CTLA-4 in their interactions with CD80 and CD86 molecules. Alternativel y, interactions may involve variants of CD28 land possibly CTLA-4) that are not recognized by certain anti-CD28 mAb.