Impaired natural killer cell self-education and "missing-self" responses in Ly49-deficient mice

Ly49-mediated recognition of MHC-I molecules on host cells is considered vital for natural killer (NK)-cell regulation and education; however, gene-deficient animal models are lacking because of the difficulty in deleting this large multigene family. Here, we describe NK gene complex knockdown (NKC^KD) mice that lack expression of Ly49 and related MHC-I receptors on most NK cells. NKC^KDNK cells exhibit defective killing of MHCI-deficient, but otherwise normal, target cells, resulting in defective rejection by NKC^KD mice of transplants from various types of MHC-I-deficient mice. Self-MHC-I immunosurveillance by NK cells in NKC ^KDmice can be rescued by self-MHC-I-specific Ly49 transgenes. Although NKC^KDmice display defective recognition of MHC-I-deficient tumor cells, resulting in decreased in vivo tumor cell clearance, NKG2D- or antibody-dependent cell-mediated cytotoxicity-induced tumor cell cytotoxicity and cytokine production induced by activation receptors was efficient in Ly49-deficient NK cells, suggesting MHC-I education of NK cells is a single facet regulating their total potential. These results provide direct genetic evidence that Ly49 expression is necessary for NK-cell education to self-MHC-I molecules and that the absence of these receptors leads to loss of MHC-I-dependent "missing-self" immunosurveillance by NK cells.