The mechanism behind natural tumor resistance conveyed by a H-2Dd transgene to C57Bl/6 (B6) mice was investigated. Transgenic D8 mice were more efficient than control mice in natural killer (NK) cell mediated rapid elimination of intravenously inoculated radiolabeled lymphoma cells of B6 origin, such as RBL-5. There was no difference between D8 and B6 mice when elimination of YAC-1 targets was monitored. The effect of the transgene on the NK repertoire was related to the H-2 phenotype of the target: the differential elimination of RBL-5 lymphoma cells in D8 and B6 mice was not seen when a H-2 deficient variant of this line was used (efficiently eliminated in both genotypes), nor was it seen with a H-2Dd transfectant (surviving in both genotypes). The data show that a MHC class I transgene can directly control natural killing in vivo by altering the repertoire rather than the general levels of NK activity. Since the NK mediated elimination seen after introduction of a novel gene in the host was neutralized by introducing the same gene (H-2Dd), but not an unrelated class I gene (H-2Dp), in the tumor, the data support the concept of NK surveillance against missing self. This combined transgenic/transfectant system may serve as a tool for a molecular dissection of the interactions between NK cells and their targets in vivo.

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