Crucial Role of DNA Methylation in Determination of Clonally Distributed Killer Cell Ig-like Receptor Expression Patterns in NK Cells

Santourlidis, Simeon; Trompeter, Hans-Ingo; Weinhold, Sandra; Eisermann, Britta; Meyer, Klaus L.; Wernet, Peter; Uhrberg, Markus

doi:10.4049/jimmunol.169.8.4253

Cited by 223 publications

(227 citation statements)

References 59 publications

Supporting

Mentioning

218

Contrasting

Unclassified

Order By: Relevance

“…This control could be due to global gene regulatory mechanisms. The idea of global transcriptional regulation of the KIR gene cluster is supported by the observations of Santourlidis and colleagues (53). They observed that demethylating treatment of NK cells resulted in the de novo expression of various variegated KIR.…”

Section: Figure 3 (Continues)supporting

confidence: 65%

Different and Divergent Regulation of the KIR2DL4 and KIR3DL1 Promoters

Stewart

Bergen

Trowsdale

2003

The Journal of Immunology

View full text Add to dashboard Cite

The killer Ig-like receptors (KIR) are a family of highly related MHC class I receptors that show extreme genetic polymorphism both within the human population and between closely related primate species, suggestive of rapid evolutionary diversification. Most KIR are expressed in a variegated fashion by the NK population, giving rise to an NK repertoire of specificities for MHC class I. We compared the promoter for KIR3DL1, which exhibits variegated gene expression, with that for KIR2DL4, which is expressed by all NK cell clones. Maximum transcriptional activity of each was encoded within ∼270 bp upstream of the translation initiation codon. The KIR2DL4 promoter drove reporter gene expression only in NK cells, while the KIR3DL1 promoter was active in a range of cell types, suggesting that the latter requires other regulatory elements for physiological expression. In NK cells, reporter gene expression driven by the KIR2DL4 promoter was greater than that driven by the KIR3DL1 promoter. DNase I footprinting revealed that transcription factor binding sites differ between the two promoters. The data indicate that while the promoters of these two KIR genes share 67% nucleotide identity, they have evolved distinct properties consistent with different roles in regulating the generation of NK repertoire.

show abstract

Section: Figure 3 (Continues)supporting

confidence: 65%

Different and Divergent Regulation of the KIR2DL4 and KIR3DL1 Promoters

Stewart

Bergen

Trowsdale

2003

The Journal of Immunology

View full text Add to dashboard Cite

show abstract

“…However, the mechanisms underlying NK-cell education are still controversially debated. On the one hand, it has been proposed that engagement of self-MHC-specific inhibitory receptors directly confers functionality to NK cells, a process that is referred to as ''licensing'' [3, 7] Overall, these data demonstrate that cytokines are indeed able to induce a rather stable expression of KIR on a subpopulation of KIR À NKG2A À NK cells and of NKG2A on the majority of cells in the absence of accessory cells.Cytokine-induced KIR3DL1 expression is associated with epigenetic changes in its gene promoter Clonal patterns of KIR expression are mainly epigenetically determined and maintained through DNA methylation [11,12]. Therefore, if cytokine-induced expression of KIR was stable, NK cells that expressed KIR after IL-2 stimulation should display hypomethylated CpG in its corresponding KIR gene promoter, similar to what has been shown for the ex vivo KIR 1 NK cells.…”

mentioning

confidence: 54%

“…Cytokine-induced KIR3DL1 expression is associated with epigenetic changes in its gene promoter Clonal patterns of KIR expression are mainly epigenetically determined and maintained through DNA methylation [11,12]. Therefore, if cytokine-induced expression of KIR was stable, NK cells that expressed KIR after IL-2 stimulation should display hypomethylated CpG in its corresponding KIR gene promoter, similar to what has been shown for the ex vivo KIR 1 NK cells.…”

mentioning

confidence: 54%

“…Clonal patterns of KIR expression are mainly epigenetically determined and maintained through DNA methylation [11,12] The KIR3DL1 promoter of ex vivo KIR À NKG2A À NK cells was predominantly methylated at almost all CpG positions analyzed, while the one of ex vivo KIR3DL1 1 was significantly but not completely hypomethylated (Fig. 3A and Supporting Information Fig.…”

Section: Cytokine-induced Kir3dl1 Expression Is Associated With Epigementioning

confidence: 99%

“…Bisulfite conversion was performed using an EpiTect Bisulfite Kit (Qiagen) reaching a conversion efficiency of 499%. The bisulfite converted DNA was amplified by PCR using KIR3DL1 primers as published previously [11]. Amplicons were cloned using a TA-TOPO cloning Kit (Invitrogen, Germany) and from each donor at least 22 clones per NK-cell subset were sequenced using vector-based M13 reverse (À29) primer and aligned to the genomic sequence of KIR3DL1 using the NCBI blast tool.…”

Section: Dna Methylation Analysismentioning

confidence: 99%

See 2 more Smart Citations

Education of hyporesponsive NK cells by cytokines

et al. 2009

View full text Add to dashboard Cite

NK-cell tolerance to self is mediated via engagement of inhibitory receptors by cognate MHC molecules. This event is critical for NK-cell education to achieve functional competence. Thus, NK cells expressing self-MHC-specific inhibitory receptors are responsive to activating stimuli while those lacking such receptors are hyporesponsive. Nevertheless, the mechanisms underlying NK-cell education are still poorly understood. Here, we show that after stimulation with cytokines, hyporesponsive NK cells acquire stable expression of killer Ig-like receptors (KIR) as reflected by DNA hypomethylation of their KIR locus. Remarkably, only hyporesponsive NK cells that acquire KIR in the presence of their cognate MHC molecule gain functional competence and this process can occur in the absence of any accessory cells. Acquisition of competence does not result in autoreactivity, since acquired KIR are functional and therefore able to inhibit NK-cell cytotoxicity. Our data demonstrate that competent NK cells can be generated by cytokine stimulation, suggesting that NK-cell education might not only be an early event which takes place during NK-cell development but might also occur in the periphery during an immune response.Key words: Education . Killer Ig-like receptors . MHC . NK cells . Tolerance Supporting Information available onlineIntroduction NK cells are bone-marrow derived lymphocytes which play an important role in mediating innate immune responses to viruses, tumors and MHC-mismatched bone marrow grafts. The main effector functions of NK cells, such as cytokine production and cytotoxicity, are tightly regulated by a balance between activating and inhibitory signals. After engagement of multiple activating receptors expressed on their surface, NK cells can produce IFN-g and kill target cells. In most cases, ligands for activating receptors are pathogen-encoded molecules or self-proteins whose expression is up-regulated in transformed or infected cells. However, even normal cells can be lysed by NK cells if they fail to express a full set of self-MHC class I proteins [1]. These observations highlight NK-cell potential autoreactivity and raise the question of how NK cells discriminate diseased cells from healthy ones. NK cells are self-tolerant because they express inhibitory receptors specific for distinct polymorphic variants of MHC class I molecules which counteract the activating signals. Inhibitory receptors include the killer Ig-like receptors (KIR) in humans, the lectin-like Ly49 dimers in mice and the lectin-like CD94/NKG2A heterodimers in both species. Interestingly, the genes for inhibitory receptors and their cognate MHC class I ligands segregate independently, so genetic mechanisms cannot ensure that each NK-cell inhibitory receptor encounters its specific self-MHC class I molecule [2]. In line with this fact, some NK cells exist, which do not express any self-MHC class I-specific inhibitory receptor. However, 2548such NK cells are self-tolerant because they are hyporesponsive after engagement of activating ...

show abstract

Do hypomethylating agents prevent relapse after Allo-HCT?

et al. 2018

View full text Add to dashboard Cite

Relapse is the main cause of treatment failure in patients with acute myeloid leukemia (AML) and myelodysplastic syndromes (MDS) and limits the curative potential of allogeneic blood stem cell transplantation (allo-HCT). Many patients can either not tolerate or do not achieve durable remissions through commonly used treatment options such as salvage chemotherapy, donor lymphocyte infusions (DLI), and/or second transplants. Thus, patients who relapse after allo-HCT have a very poor prognosis with the currently available therapies implicating the great medical need for relapse prevention. After having demonstrated efficacy and tolerability as salvage therapy in patients with myeloid malignancies who relapse after allo-HCT the hypomethylating agents azacitidine (Aza) and decitabine (DAC) have also been tested as prophylactic and preemptive approaches in patients with AML and MDS after allo-SCT. Here, we summarize the current literature reporting on results from prospective trials and retrospective analyses regarding the prophylactic and preemptive use of Aza and DAC after allo-SCT and aim to give an answer if these hypomethylating agents (HMA) are able to prevent relapse of myeloid malignancies after allo-HCT. K E Y W O R D Sacute myeloid leukemia, allogeneic transplantation, azacitidine, decitabine, maintenance, myelodysplastic syndromes, relapse

show abstract

Crucial Role of DNA Methylation in Determination of Clonally Distributed Killer Cell Ig-like Receptor Expression Patterns in NK Cells

Cited by 223 publications

References 59 publications

Different and Divergent Regulation of the KIR2DL4 and KIR3DL1 Promoters

Different and Divergent Regulation of the KIR2DL4 and KIR3DL1 Promoters

Education of hyporesponsive NK cells by cytokines

Do hypomethylating agents prevent relapse after Allo-HCT?

Contact Info

Product

Resources

About