MHC CLASS-I ALLOANTIGEN SPECIFICITY OF LY-49+ IL-2-ACTIVATED NATURAL-KILLER-CELLS

THE molecular basis of target cell recognition by CD3- natural killer (NK) cells is poorly understood, despite the ability of NK cells to lyse specific tumour cells 1,2. In general, target cell major histocompatibility complex (MHC) class I antigen expression correlates with resistance to NK cell-mediated lysis 3-9, possibly because NK cell-surface molecules engage MHC class I antigens and consequently deliver inhibitory signals 3,4. Natural killer cell allospecificity involves the MHC class I peptide-binding cleft 10, and further understanding of this allospecificity should provide insight into the molecular mechanisms of NK cell recognition. The Ly-49 cell surface molecule is expressed by 20% of CD3- NK cells 11 in C57BL/6 mice (H-2b). Here we show that C57BL/6-derived, interleukin-2-activated NK cells expressing Ly-49 do not lyse target cells displaying H-2d or H-2k despite efficient spontaneous lysis by Ly-49- effector cells. This preferential resistance correlates with expression of target cell MHC class I antigens. Transfection and expression of H-2D(d), but not H-2K(d) or H-2L(d), renders a susceptible target (H-2b) resistant to Ly-49+ effector cells. The transfected resistance is abrogated by monoclonal antibodies directed against Ly-49 or the alpha-1/alpha-2 domains of H-2D(d), suggesting that Ly-49 specifically interacts with the peptide-binding domains of the MHC class I alloantigen, H-2D(d) Inas-much as Ly49+ effector cells cannot be stimulated to lyse H-2D(d) targets, our results indicate that NK cells may possess inhibitory receptors that specifically recognize MHC class I antigens.