title: NK-mediated elimination of mutant lymphocytes that have lost expression of MHC class I molecules.
abstract: Mutant cells generated in vivo can be eliminated when mutated gene products are presented as altered MHC/peptide complexes and recognized by T cells. Diminished expression of MHC/peptide complexes enables mutant cells to escape recognition by T cells. In the present study, we tested the hypothesis that mutant lymphocytes lacking expression of MHC class I molecules are eliminated by autologous NK cells. In H-2b/k F1 mice, the frequency of H-2Kb-negative T cells was higher than that of H-2Kk-negative T cells. The frequency of H-2K-deficient T cells increased transiently after total body irradiation. During recovery from irradiation, H-2Kk-negative T cells disappeared more rapidly than H-2Kb-negative T cells. The disappearance of H-2K-deficient T cells was inhibited by administration of Ab against asialo-GM1. H-2Kk-negative T cells showed higher sensitivity to autologous NK cells in vitro than H-2Kb/k heterozygous or H-2Kb-negative T cells. Adding syngeneic NK cells to in vitro cultures prevented emergence of mutant cells lacking H-2Kk expression but had little effect on the emergence of mutant cells lacking H-2Kb expression. Results in the H-2b/k F1 strain correspond with the sensitivity of parental H-2-homozygous cells in models of marrow graft rejection. In H-2b/d F1 mice, there was no significant difference between the frequencies of H-2Kb-negative and H-2Kd-negative T cells, although the frequencies of mutant cells were different after radiation exposure among the strains examined. H-2b/d F1 mice also showed rapid disappearance of the mutant T cells after irradiation, and administration of Ab against asialo-GM1 inhibited the disappearance of H-2K-deficient T cells in H-2b/d F1 mice. Our results provide direct evidence that autologous NK cells eliminate mutant cell populations that have lost expression of self-MHC class I molecules.
authors.affiliation: Department of Radiobiology, Radiation Effects Research Foundation, Minami Ward, Hiroshima, Japan. ykusunok@rerf.or.jp
authors.forename: Y
authors.initials: Y
authors.lastname: Kusunoki
authors.forename: S
authors.initials: S
authors.lastname: Kyoizumi
authors.forename: M
authors.initials: M
authors.lastname: Honma
authors.forename: Y
authors.initials: Y
authors.lastname: Kubo
authors.forename: H
authors.initials: H
authors.lastname: Ohnishi
authors.forename: T
authors.initials: T
authors.lastname: Hayashi
authors.forename: T
authors.initials: T
authors.lastname: Seyama
mesh_terms: D000818:Animals; D002470:Cell Survival / Q000235:genetics / Q000276:immunology / Q000528:radiation effects; D002478:Cells, Cultured; D003433:Crosses, Genetic; D003602:Cytotoxicity, Immunologic / Q000235:genetics; D005677:G(M1) Ganglioside / Q000276:immunology; D005786:Gene Expression Regulation / Q000235:genetics / Q000276:immunology / Q000528:radiation effects; D005805:Genes, MHC Class I / Q000528:radiation effects; D006183:H-2 Antigens / Q000096:biosynthesis* / Q000235:genetics* / Q000528:radiation effects; D007106:Immune Sera / Q000008:administration & dosage; D007694:Killer Cells, Natural / Q000276:immunology*; D018655:Lymphocyte Count; D008212:Lymphocyte Depletion; D051379:Mice; D008807:Mice, Inbred BALB C; D008809:Mice, Inbred C3H; D008810:Mice, Inbred C57BL; D008811:Mice, Inbred DBA; D008814:Mice, Inbred NZB; D009154:Mutation / Q000276:immunology*; D011828:Radiation Chimera / Q000276:immunology; D016176:T-Lymphocyte Subsets / Q000276:immunology* / Q000378:metabolism / Q000528:radiation effects
chemical_list: D006183:H-2 Antigens; C024755:H-2K(K) antigen; C032876:H-2Kb protein, mouse; D007106:Immune Sera; D005677:G(M1) Ganglioside; C018835:asialo GM1 ganglioside