SPECIFIC FUNCTIONS OF HUMAN NK CELLS

Since natural killer (NK) cells lack both CD3/TCR molecules and surface Ig, it is generally thought that they are unable to recognize antigens. However, CD3-CD16+ cells were found to respond in MLC against irradiated allogeneic mononuclear cells and to lyse normal PHA blasts derived from the stimulating donor, but not autologous cells or cells derived from most allogeneic donors. A similar pattern was obtained with cloned NK cells, thus indicating that the ability to specifically recognize given normal allogeneic cells is a clonally distributed function. Moreover, analysis of NK clones for their ability to lyse either tumor cells or normal PHA blasts (both derived from individual cancer patients) indicated that the two phenomena are distinct. Analysis of a large number of NK clones derived from a given individual for their ability to lyse a panel of allogeneic donors allowed the identification of at least four groups of clones characterized by unique patterns of reactivity ("specificities"). We further studied the mode of inheritance of the various NK-defined specificities: all the characters "susceptibility to lysis" by NK clones (displaying one or another specificity) segregated independently, were inherited in an autosomic recessive manner and were carried by chromosome 6. The finding of clonally distributed specific functions in NK cells suggested the existence of clonally distributed receptor molecules. Along this line, mAbs were raised against NK clones, and screened for their ability to trigger the immunizing clones: two mAbs (termed GL183 and EB6) were directed against a novel family of 58-kDa surface molecules. On the basis of the surface distribution of the corresponding molecules it has been possible to define four distinct NK subsets (EB6+GL183 -, EB6+GL183+, EB6-GL183+, EB6-GL183-). More importantly, the analysis of a large number of clones demonstrated a striking correlation between the EB6+GL183- subset and the reactivity against the first-defined specificity. Similar phenotypic homogeneity was revealed for clones belonging to other groups of specificities, thus suggesting that the GL183/EB6 molecular family may be involved in the specific recognition of alloantigens mediated by NK cells.