DNA Methylation Maintains Allele-specific KIR Gene Expression in Human Natural Killer Cells (original) (raw)
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European Journal of Immunology, 2007
NK cells detect altered patterns of HLA expression in infections and tumors using a variegated repertoire of killer cell Ig-like receptors (KIR). Each clone surveys different HLA molecules by expressing a limited subset of the KIR encoded in its genome, which is maintained throughout cell divisions by epigenetic mechanisms (methylation of the nonexpressed genes). How KIR repertoires are acquired remains, however, unexplained. Human KIR2DL5 is a useful model for studying KIR expression because it has alleles with similar coding regions, but drastically divergent expression-whilst some are transcribed in a typically clonal manner, others, with distinctive promoter polymorphisms, are nonexpressed. Here we investigate the relationship between the sequence diversity of KIR2DL5, including three novel alleles, and its variable transcription. The promoters of the transcribed alleles recruit the transcriptional regulator RUNX3, whilst a mutation shared by all silent alleles precludes this binding. However, all promoters are functional in vitro, and pharmacological DNA demethylation of NK cells rescues the transcription of silent alleles, indicating that only epigenetic mechanisms prevent their inclusion in a normal KIR repertoire. Our results are consistent with a model in which RUNX factors could function as switch elements in the acquisition of KIR repertoires by NK cell precursors.
Journal of immunology (Baltimore, Md. : 1950), 2008
The clonal distribution and stable expression of killer cell Ig-like receptor (KIR) genes is epigenetically regulated. To assess the epigenetic changes that occur during hemopoietic development we examined DNA methylation and chromatin structure of the KIR locus in early hemopoietic progenitor cells and major lymphocyte lineages. In hemopoietic progenitor cells, KIR genes exhibited the major hallmarks of epigenetic repression, which are dense DNA methylation, inaccessibility of chromatin to Micrococcus nuclease digest, and a repressive histone signature, characterized by strong H3K9 dimethylation and reduced H4K8 acetylation. In contrast, KIR genes of NK cells showed active histone signatures characterized by absence of H3K9 dimethylation and presence of H4K8 acetylation. Histone modifications correlated well with the competence of different lymphocyte lineages to express KIR; whereas H4K8 acetylation was high in NK and CD8+ T cells, it was almost absent in CD4+ T cells and B cells ...
The Journal of experimental medicine, 2015
The fidelity of T cell immunity depends greatly on coupling T cell receptor signaling with specific T cell effector functions. Here, we describe a chromatin-based mechanism that enables integration of TCR specificity into definite T cell lineage commitment. Using natural killer T cells (iNKT cell) as a model of a T cell subset that differentiates in response to specific TCR signaling, we identified a key role of histone H3 lysine 27 trimethylation (H3K27me3) in coupling iNKT cell TCR specificity with the generation of iNKT cells. We found that the Zbtb16/PLZF gene promoter that drives iNKT cell differentiation possesses a bivalent chromatin state characterized by the simultaneous presence of negative and positive H3K27me3 and H3K4me3 modifications. Depletion of H3K27me3 at the Zbtb16/PLZF promoter leads to uncoupling of iNKT cell development from TCR specificity and is associated with accumulation of iNKT-like CD4(+) cells that express a non-iNKT cell specific T cell repertoire. In ...
Journal of Experimental Medicine
Natural killer (NK) cells that express the NKB1 receptor are inhibited from killing target cells that possess human histocompatibility leukocyte antigen (HLA) B molecules bearing the Bw4 serological epitope. To investigate whether NKB1 expression is affected by HLA type, peripheral blood lymphocytes of 203 HLA-typed donors were examined. Most donors had a single population ofNKB1 + cells, but some had two populations expressing different cell surface levels of NKB 1, and others had no detectable NKB 1 + cells. Among the donors expressing NKB 1, both the relative abundance of NKB 1 + NK cells and their level of cell surface expression varied substantially. The percentage of NKB1 + NK cells ranged from 0 to >75% (mean 14.7%), and the mean fluorescence of the positive population varied over three orders of magnitude. For each donor, the small percentage ofT cells expressing NKB1 (usually <2%), had a pattern of expression mirroring that of the NK cells. NKB1 expression by NK and T cells remained stable over the 2-yr period that five donors were tested. Patterns of NKB1 expression were not associated with Bw4 or Bw6 serotype of the donor or with the presence of any individual HLA-A or -B antigens. Cells expressing NKB 1 are often found in donors who do not possess an appropriate class I ligand, and can be absent in those who express Bw4 + HLA-B antigens. Family studies further suggested that the phenotype of NKB1 expression is inherited but not HLA linked. Whereas identical twins show matching patterns of NKB 1 expression, HLA-identical siblings can differ in NKB1 expression, and conversely, HLA-disparate siblings can be similar. Thus NKB1 expression phenotypes are tightly regulated and extremely heterogenous, but not correlated with HLA type.
Journal of Experimental Medicine, 1996
Natural killer (NK) cells that express the NKB1 receptor are inhibited from killing target cells that possess human histocompatibility leukocyte antigen (HLA) B molecules bearing the Bw4 serological epitope. To investigate whether NKB1 expression is affected by HLA type, peripheral blood lymphocytes of 203 HLA-typed donors were examined. Most donors had a single population ofNKB1 + cells, but some had two populations expressing different cell surface levels of NKB 1, and others had no detectable NKB 1 + cells. Among the donors expressing NKB 1, both the relative abundance of NKB 1 + NK cells and their level of cell surface expression varied substantially. The percentage of NKB1 + NK cells ranged from 0 to >75% (mean 14.7%), and the mean fluorescence of the positive population varied over three orders of magnitude. For each donor, the small percentage ofT cells expressing NKB1 (usually <2%), had a pattern of expression mirroring that of the NK cells. NKB1 expression by NK and T cells remained stable over the 2-yr period that five donors were tested. Patterns of NKB1 expression were not associated with Bw4 or Bw6 serotype of the donor or with the presence of any individual HLA-A or -B antigens. Cells expressing NKB 1 are often found in donors who do not possess an appropriate class I ligand, and can be absent in those who express Bw4 + HLA-B antigens. Family studies further suggested that the phenotype of NKB1 expression is inherited but not HLA linked. Whereas identical twins show matching patterns of NKB 1 expression, HLA-identical siblings can differ in NKB1 expression, and conversely, HLA-disparate siblings can be similar. Thus NKB1 expression phenotypes are tightly regulated and extremely heterogenous, but not correlated with HLA type.
Ly49 receptor genes are expressed by subsets of natural killer (NK) cells in an overlapping fashion, accounting for the capacity of NK subsets to attack host cells that have selectively downregulated self-major histocompatibility complex (MHC) class I molecules. It was shown previously that most NK cells express only one or the other allele of a given Ly49 gene, while a smaller population expresses both alleles. However, the methods used to detect monoallelic and biallelic cells were nonquantitative. Here, new allele-specific antibodies were used to provide the first quantitative examination of biallelic and monoallelic expression of Ly49A and Ly49G2. The results demonstrate conclusively that most Ly49A ϩ and Ly49G2 ϩ NK cells express the corresponding gene in a monoallelic fashion, with a smaller subset expressing both alleles. Unexpectedly, biallelic Ly49A ϩ NK cells were more numerous than predicted by completely independent allelic expression, suggesting some heterogeneity among NK progenitors in the potential to express a given Ly49 gene. The data also show that cells expressing one allele of Ly49G2 may express Ly49A from the same or opposite chromosome with equal likelihood, indicating that the expressed allele is chosen independently for different Ly49 genes. Finally, the data demonstrate that biallelic expression of Ly49A or Ly49G2 occurs least frequently in mice that express ligands for these receptors (H-2 d mice), and most frequently in class I-deficient mice. Thus, biallelic expression of Ly49 genes is regulated by interactions of NK cell progenitors with MHC class I molecules.
Journal of Experimental Medicine, 1993
As ancestral haplotypes of the major histocompatibility complex (MHC) appear to define identical MHC haplotypes in unrelated individuals, unrelated individuals sharing the same ancestral haplotype should also share the same NK-defined allospecificities that have recently been shown to map to the human MHC. To test this prediction, multiple cell lines from unrelated individuals sharing the same ancestral haplotypes were tested for the NK-defined allospecificities. It was found that cells sharing the same ancestral haplotypes do have the same NK-defmed specificities. Furthermore, the NK-defined phenotype of ceUs that possess two different ancestral haplotypes can be predicted from the NK-defined phenotypes of unrelated cells that are homozygous for the ancestral haplotypes concerned. Although the group 1 and 2 NK-defined allospecificities can be explained to some extent by HLA-C alleles, evidence is presented that additional genes may modify the phenotype conferred by HLA-C.
Journal of Experimental Medicine, 2006
Interactions between killer cell immunoglobulin-like receptors (KIRs) and human leukocyte antigen (HLA) class I ligands regulate the development and response of human natural killer (NK) cells. Natural selection drove an allele-level group A KIR haplotype and the HLA-C1 ligand to unusually high frequency in the Japanese, who provide a particularly informative population for investigating the mechanisms by which KIR and HLA polymorphism influence NK cell repertoire and function. HLA class I ligands increase the frequencies of NK cells expressing cognate KIR, an effect modified by gene dose, KIR polymorphism, and the presence of other cognate ligand–receptor pairs. The five common Japanese KIR3DLI allotypes have distinguishable inhibitory capacity, frequency of cellular expression, and level of cell surface expression as measured by antibody binding. Although KIR haplotypes encoding 3DL1*001 or 3DL1*005, the strongest inhibitors, have no activating KIR, the dominant haplotype encodes ...