Role of major histocompatibility complex class I alpha 1/alpha 2 domain polymorphism and in vivo expression pattern in tumor resistance: studies with transgenic mice and lymphoma cell transfectants.
The influence of major histocompatibility complex (MHC) class I molecules on target cell sensitivity and natural killer cell specificity was investigated. H-2b lymphoma cells grew progressively in syngeneic nontransgenic C57Bl/6 (B6) mice, but were rapidly rejected (within 24 h) in H-2Dd transgenic B6 mice (D8). Rejection required transgene expression in hematopoietic tissues, as revealed in experiments using transgenic mice with tissue-specific expression of the transgene into the target cells as well as bone marrow chimeric mice. The rejection was abrogated by transfection of the H-2Dd gene, providing evidence of "missing self" recognition in vivo triggered by a single class I allelic difference between host and graft. Lymphoma cells transfected with nonrelated class I molecules (H-2Dp and H-2Ld) did not lead to escape from rejection in D8 mice. Furthermore, transfection with exon shuffled constructs between H-2Dd and H-2Ld allowed mapping of the "protective" parts of H-2Dd. Only the transfectant expressing the alpha 1/alpha 2 domains of H-2Dd (the alpha 3 domain of H-2Ld) escaped elimination in D8 mice, while the transfectant expressing the opposite exon shuffled gene (the alpha 1/alpha 2 domains of H-2Ld in connection with the alpha 3 domain of H-2Dd) was rejected like the nontransfected wild type. The results showed that (a) introduction of a novel MHC class I gene in transgenic mice altered the specificity of natural killer cells, and (b) protection from transgenic NK cells required expression of the alpha 1/alpha 2 domains of H-2Dd at the target level.
Höglund
P
P
Department of Tumor Biology, Karolinska Institutet, Stockholm, Sweden.
Waldenström
M
M
Kärre
K
K
D000483:Alleles; D000818:Animals; D015870:Gene Expression; D015395:Histocompatibility Antigens Class I / Q000235:genetics*; D007113:Immunity, Innate; D007694:Killer Cells, Natural / Q000276:immunology; D008223:Lymphoma / Q000235:genetics* / Q000473:pathology; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D008968:Molecular Conformation; D011110:Polymorphism, Genetic; D014162:Transfection; D014407:Tumor Cells, Cultured
D015395:Histocompatibility Antigens Class I