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–2 b ). Here we show that C57BL/6-derived, interleukin-2-activated NK cells expressing Ly-49 do not lyse target cells displaying H–2 d or H–2 k 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–2 b ) resistant to Ly-49 + effector cells. The transfected resistance is abrogated by monoclonal anti-bodies directed against Ly-49 or the α1/α2 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 Ly-49 + 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.