Recognition of β2-microglobulin-negative (β2m-) T-cell blasts by natural killer cells from normal but not from β2m- mice: Nonresponsiveness controlled by β2m- bone marrow in chimeric mice

Abstract

The role of major histocompatibility complex (MHC) class I expression in control of the sensitivity of normal cells to natural killer (NK) cells was studied by the use of mutant mice made deficient for expression β2-microglobulin (β2m) through homologous recombination in embryonal stem cells. T-cell blasts from β2m-deficient (β2m -/-) mice were killed by NK cells from normal mice in vitro, while β2m +/-blasts were resistant. The β2m defect also affected the NK effector cell repertoire: NK cells from β2m -/- mice failed to kill β2m -/- blasts, while they retained the ability to kill the prototype NK cell target lymphoma YAC-1, although at reduced levels. The inability to recognize β2m -/- blasts could be transferred with β2m -/- bone marrow to irradiated β2m-expressing mice. In contrast, the development of CD8+ T cells (deficient in β2m -/- mice) was restored in such chimera. These results indicate that loss of MHC class I/β2m expression is sufficient to render normal cells sensitive to NK cells, and that the same defect in the hemopoietic system of a mouse renders its NK cells tolerant to /β2m-deficient but otherwise normal cells. In the β2m -/- mice, NK cells may be selected or educated by other bone marrow cells to tolerate the MHC class I deficiency. Alternatively, the specificity may be controlled directly by the class I molecules on the NK cells themselves.