NK cell receptor calibration: effects of MHC class I induction on killing by Ly49Ahigh and Ly49Alow NK cells.

NK cells from C57BL/6 (B6) mice and H-2Dd transgenic B6 (D8) mice express different levels of the inhibitory receptor Ly49A, and they also differ in their target cell specificity. Here, we examined this differential specificity with respect to the role of the Ly49A receptor expression on effector cells and levels of H-2Dd inhibitory ligands on target cells. NK cells from D8 mice express low levels of Ly49A receptor (Ly49Alow), and are able to kill SP2/0 tumor cells in spite of their expression of H-2Dd. H-2Dd is expressed at reduced levels on SP2/0 cells; when these were increased three- to fivefold after IFN-gamma treatment, the killing by Ly49Alow NK cells from D8 mice was markedly reduced. Efficient killing was restored when the effectors were preincubated with anti-Ly49A F(ab')2 Abs. A separate experimental system was based on D8 TAP1-deficient Con A blasts exogenously loaded with H-2Dd-specific peptides. In this system, higher levels of cell surface H-2Dd had to be induced by peptide to inhibit D8 Ly49Alow NK cells to an extent similar to that of B6 Ly49Ahigh NK cells. Ly49A receptors on NK cells from H-2Dd transgenic mice are thus functional, although they require high levels of ligand to inhibit progression of the NK-target cell interaction. The data are in favor of the "receptor-calibration" model, which suggests that down-regulation of inhibitory receptors on NK cells may be useful in order for NK cells to discriminate between normal and reduced levels of MHC class I molecules.