| Natural killer (NK) cells were originally defined by spontaneous killing of tumor cells and certain virally infected cells without prior sensitization. The molecular basis of NK cell recognition of these target cells remains only partly understood. In the C57BL/6 mouse, the Ly-49 family of activating and inhibitory receptors, termed Ly-49A through H, appears to regulate NK cell specificity. The inhibitory Ly-49 molecules recognize MHC class I ligands, as does the activating Ly-49D receptor. However, the role of these receptors and ligands in NK cell specificity for target cells is not clear in the context of pathogen infection. To study Ly-49H expression, function and ligands, we produced the 3D10 monoclonal antibody (mAb) that binds Ly-49H and does not cross-react with additional Ly-49 molecules. Studies with mAb 3D10 show that Ly-49H is expressed only on NK cells, and that this specific NK cell expression appears to be regulated with respect to additional NK cell receptors. Ly-49H activates NK cell cytotoxicity and cytokine production, and in vivo Ly-49H is required for control of acute MCMV infection in the spleen. Using a Ly-49H transfected responder cell line, we identified ligands for Ly-49H on MCMV infected macrophages. Therefore, NK cell specificity for target cells may be regulated by innate NK cell activation receptors such as Ly-49H that recognize ligands induced upon viral infection. These observations indicate a role for NK cells as an early responding lymphocyte population, limiting the spread of viruses until antigen-specific acquired immunity can be generated. |
