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.

HIV-1 Nef: a master manipulator of the membrane trafficking machinery mediating immune evasion

“…NK cells bind to molecules on the cell surface of neighboring cells via inhibitory or activating receptors, and this balance determines NK-mediated destruction. NK cells bind specific classes of MHC-I molecules and cells lacking sufficient cell surface MHC-I molecules are often targeted for NK-mediated destruction [97]. HIV-1 infected cells avoid this fate by preferential downregulation of specific classes of MHC-I.…”

NK cell self tolerance, responsiveness and missing self recognition

“…Evidence clearly indicates that such receptors inhibit rejection of tumor cells expressing self MHC molecules [84], and previous studies show that NK cells that express inhibitory receptors for self MHC mediate the rejection of MHC I-deficient bone marrow grafts [40]. Therefore, it is reasonable to propose that these NK cells function to eliminate MHC-deficient cells that arise by mutations in normal cells [85], mutations in tumor cells, or as a result of MHC I-downregulation that occurs in certain viral infections. Such cells could also play a role (along with T cells and antibodies) in eliminating allogeneic (MHC-different) cells transferred sexually, and therefore serve to prevent tumors from becoming sexually transmissible.…”

Generation of loss of heterozygosity and its dependency on p53 status in human lymphoblastoid cells

“…Recessive mutations induced in vivo can be detected in cell types that can be isolated and grown in vitro, such as splenic T-lymphocytes or skin fibroblasts. Mutation has also been detected in mice using other genes, such as the T-cell receptor (Tcr) and some major histocompatability complex (Mhc) genes [Umeki et al, 1997;Kusunoki et al, 2000]. Although the frequencies of recessive mutation in these models depend on the gene target, the cell type, the animal species, and the detection system, LOH or allele loss is frequently observed in all of these model systems [Liber et al, 1987;Wijnhoven et al, 2001;Turker, 2003].…”