Natural Killer Cell Recognition of “Self” and “Non-Self” Triggering Antigens on Normal Lymphoblasts

NK cell specificity for normal lymphoblasts was tested in mice by direct cytotoxicity and competitive inhibition assays. IL-2-activated NK cells lysed Hh-1 incompatible but not Hh-1 compatible or Hh-1[null] allogeneic and semisyngeneic lymphoblasts. NK cells also lysed some syngeneic blasts. NK alloreactivity was inhibited by unlabeled targets which shared at least one Hh-1 determinant with the labeled target. NK self-reactivity was inhibited by syngeneic cells as well as by some allogeneic cells. Class I molecule-deficient β2m−/− blasts universally inhibited NK lysis of all normal blasts. Cold targets appeared to specifically inhibit NK lysis by competing for recognition by NK activatory receptors rather than by competing for NK lysis by sharing with hot targets the absence of MHC class I inhibitory molecules recognized by NK cell Ly49 molecules. Backcross analysis revealed that a single non-MHC-linked gene locus regulates the accessibility of some normal lymphoblast target antigens to recognition by triggering receptors on self-reactive BALB/c NK cells. The results suggest that target lymphoblast class I molecules may differentially control the accessibility of universally expressed polymorphic NK triggering antigens to positive recognition by distinct sets of alloreactive and self-reactive NK cells.