H-2 allele-specific protection from NK cell lysis in vitro for lymphoblasts but not tumor targets. Protection mediated by alpha 1/alpha 2 domains.
In vivo murine NK cells are known to mediate graft rejection in allogenic as well as in "F1 anti-parental" situations. We have studied an in vitro system based on rIL-2-activated spleen cells and Con A lymphoblast targets in relation to the genetics of F1 hybrid resistance and NK cell activity. We demonstrate that NK cells in this in vitro model are regulated by MHC class I genes in an allele-specific manner at the level of the effector and the target. Using rIL-2-activated effector cells from nude C57BL/6 (B6) and BALB/c mice, we observed no killing of MHC syngeneic lymphoblasts. However, B6 as well as BALB/c lymphoblasts were killed by effector cells from allogeneic nude mice as well as by cells from (BALB/c x B6)F1 hybrids. Experiments that used D8 mice (which carry an H-2Dd transgene on B6 background) and beta 2-m-/- mice demonstrated a direct role for MHC class I molecules at the effector as well as at the target cell level: H-2Dd transgenic effector cells with the typical NK phenotype 3A4+/CD8- killed B6 blasts, but expression of the corresponding H-2Dd transgene in the target lymphoblasts protected them from killing. By using transgenic mice carrying exon shuffled MHC class I transgenes, the protective effect of the H-2Dd molecule was mapped to the alpha 1/alpha 2 domains. MHC class I-deficient lymphoblasts from beta 2-m-/- mice were killed by effectors from all strains of mice, including those matched for MHC. The H-2 class I allele-specific protection in this in vitro assay was observed for lymphoblasts but not for tumor cells, despite the fact that these tumor cells are protected in an allele-specific manner in vivo.
Sentman
C L
CL
Microbiology and Tumor Biology Center, Karolinska Institute, Stockholm, Sweden.
Olsson
M Y
MY
Salcedo
M
M
Höglund
P
P
Lendahl
U
U
Käre
K
K
D000818:Animals; D003208:Concanavalin A / Q000494:pharmacology; D003601:Cytotoxicity Tests, Immunologic; D003602:Cytotoxicity, Immunologic / Q000276:immunology*; D006183:H-2 Antigens / Q000235:genetics*; D007376:Interleukin-2 / Q000502:physiology; D007694:Killer Cells, Natural / Q000276:immunology*; D016131:Lymphocyte Subsets / Q000276:immunology*; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D008819:Mice, Nude; D008822:Mice, Transgenic; D014162:Transfection; D014407:Tumor Cells, Cultured / Q000276:immunology*
D006183:H-2 Antigens; D007376:Interleukin-2; D003208:Concanavalin A