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Introduction of the MHC class I transgene H-2D d on C57BL/6 (B6) background conveys NK cell-mediated "missing self" reactivity against transgene-negative cells, and down-regulates expression of the inhibitory receptors Ly49A and Ly49G2 in NK cells. We here present an analysis of transgenic mice expressing chimeric H-2D d /L d MHC class I transgenes, and show that the § 1/ § 2 domains of H-2D d were necessary and sufficient to induce "missing self" recognition and to down-modulate Ly49A and Ly49G2 receptors. In contrast, trans-genes containing the § 1/ § 2 domains of H-2L d induced none of these changes, suggesting that not all MHC class I alleles in a host necessarily take part in NK cell education. The lack of effect of the § 1/ § 2 domains of H-2L d on NK cell specificity was surprising, considering that both H-2L d and H-2D d have been reported to interact with Ly49G2. Therefore, the role of H-2L d for protection against NK cells expressing Ly49G2 was re-investigated in a transfec-tion system. In contradiction to earlier reports, we show that H-2D d , but not H-2L d , abolished killing by sorted Ly49G2 + NK cells, indicating that H-2L d does not inhibit NK cells via the Ly49G2 receptor.

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The effect of tissue-specific expression of the MHC class I molecule H-2D(d) on T cell and NK cell specificity was studied in transgenic mice expressing the H-2D(d) gene under the control of the mouse metallothionein-I promoter. MTD mice expressed high amounts of H-2D(d) in the liver, intestine and testis, but only minute amounts in the thymus, spleen and kidney. Zinc administration resulted in a 1.5- and 8.5-fold increase in H-2D(d) expression in the liver and the intestine, respectively, but did not affect expression in the other organs tested. T cell tolerance developed towards H-2D(d) in MTD mice, even in the absence of zinc. In contrast, NK cell-mediated natural resistance against lymphoma grafts was not seen in MTD mice, despite zinc administration. NK cells in MTD mice also failed to develop self tolerance to H-2D(d). The lack of functional effects did not result from inability of NK cells in MTD mice to interact with H-2D(d), as down-regulation of Ly49A receptor expression was observed on liver NK cells in MTD mice. Our data reveal a difference between T cells and NK cells in their requirements for MHC class I molecules in specificity development.