TAP1 −/−, β2‐microglobulin (β2m) −/− and TAP1/β2m −/− mice all express low but quantitatively different levels of MHC class I molecules. Using these mice, we have addressed questions relating to the fine tuning of natural killer (NK) cell specificity and maintenance of self tolerance in the NK cell system. NK cells from B6 wild‐type mice killed target cells from TAP1 −/−, β2m −/− and TAP1/β2m −/− mice in vivo and rejected bone marrow grafts from the same mice in vivo at equivalent levels. NK cells from TAP1 −/−, β2m −/− mice did not kill target cells or reject bone marrow grafts from TAP1/β2m −/− mice. NK cells in all MHC class I‐deficient mice were tolerant to autologous MHC class I‐deficient cells, as revealed by in vitro cytotoxicity assays using NK cell effectors activated with the interferon‐inducing agent Tilorone, or by in vivo bone marrow graft experiments. However, the self‐tolerant state of MHC class I‐deficient NK cells was broken by in vitro stimulation with IL‐2 for 4 days. Under these conditions, NK cells from the MHC class I‐deficient mice killed autologous MHC class I‐deficient cells while MHC class I‐positive targets were spared. The C‐type lectin inhibitory receptor Ly49C has a specificity for H‐2Kb and is expressed on a subset of NK1.1+ cells in B6 mice. Wild‐type and all MHC class I‐deficient mice had similar numbers of Ly49C‐positive NK1.1+ cells. However, Ly49C expression was markedly down‐regulated on NK1.1+ cells from B6 mice, as compared to TAP1 −/−, β2m −/− and TAP1/β2m −/− mice. In vitro stimulation of NK cells with IL‐2 for 4 days did not significantly change this pattern. The present results are discussed in relation to the role of MHC class I molecules and Ly49 receptors in shaping the NK cell repertoire and raise new questions about maintenance of self tolerance in the NK cell system.

We have analyzed lymphocyte development in natural MHC class I chimeric mice, generated through a transgenic approach in β2-microglobulin (β2m)−/− mice. In these mice, MHC class I+ cells coexist with an equal proportion of MHC class I-deficient cells. These MHC class I mosaic mice had normal numbers of CD8+ T cells, which had a target cell specificity similar to that of wild-type mice. Consequently, the mice did not develop any signs of autoimmunity. They also had normal numbers of NK cells. This allowed an examination of the MHC class I influence on the expression of the Ly49C inhibitory receptor on NK cells. This receptor binds to H-2Kb. It is expressed at low levels on NK cells in wild-type mice of the H-2b haplotype, but at markedly higher levels on NK cells in β2m−/− mice and other strains of mice lacking expression of H-2Kb. Relatively little is known about how MHC class I molecules affect expression of the Ly49 receptors. Through the analysis of the present MHC class I mosaic mice, we demonstrate that the expression levels of Ly49C on NK cells is a consequence not only of MHC class I expression in the environment, but also of the expression of MHC class I molecules by the NK cells themselves. These findings are discussed in relation to the biological role of the calibration of the Ly49 inhibitory receptor expression in relation to self-MHC class I.