EZH2 identifies the precursors for trained immunity of human natural killer cells
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ABSTRACT:
ORGANISM(S): Homo sapiens
PROVIDER: GSE158349 | GEO | 2020/09/23
REPOSITORIES: GEO
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Project description:Trained immunity of natural killer (NK) cells has shown great potential in the treatment of cancers by eliciting enhanced effector responses to restimulation by cytokines or cancer cells for long time periods after preactivation. However, the human NK cells responsible for the generation and maintenance of trained immunity are largely unknown. We hypothesized that heterogeneous human NK cells would respond differentially to stimulation with a combination of IL-12, IL-15, and IL-18, and that an NK cell subset might exist that is mainly responsible for the induction of trained immunity. On the basis of our hypothesis, we aimed to identify the subset from which cytokine-trained human NK cells originate and to explore possible regulatory targets for drug intervention. Flow cytometry assays were performed to analyze the functions of cytokine-trained NK cells and examine cell division and protein expression in NK cell subsets. Single-cell RNA sequencing (scRNA-seq) plus TotalSeq™ technology was used to track the heterogeneity of NK cells during the induction of trained immunity. Traditional developmental markers for peripheral NK cells were unable to identify the precursors of human NK cells with trained immunity. Therefore, we used scRNA-seq plus TotalSeq™ technology to track the heterogeneity of NK cells during the induction of trained immunity and identified a unique cluster of CD57-NKG2A+EZH2+IFNG+MKI67+IL12R+IL15R+IL18R+ NK cells. Enrichment and pseudotime trajectory analyses suggested that this cluster of NK cells contained the precursor of trained NK cells. We then used flow cytometry to further investigate the role of EZH2 in trained NK precursors and found that CD57-NKG2A+EZH2+ NK cells had faster cell cycles and an enhanced trained phenotype, and EZH2 inhibition significantly impaired the induction of trained immunity in NK cells. These results suggested that EZH2 is a unique epigenetic marker of precursors of human NK cells with trained immunity. Our work revealed human NK heterogeneity in the induction of trained immunity, identified the precursor subset for trained NK cells, and demonstrated the critical role of EZH2 in the induction of trained immunity in human NK cells.
| S-EPMC8610163 | biostudies-literature
Project description:EZH2 identifies the precursors for trained immunity of human natural killer cells
| PRJNA664944 | ENA
Project description:Natural killer (NK) cells are innate lymphocytes important for early host defense against infectious pathogens and surveillance against malignant transformation. Resting murine NK cells regulate the translation of effector molecule mRNAs (e.g. granzyme B, GzmB) through unclear molecular mechanisms. MicroRNAs (miRNAs) are small non-coding RNAs that post-transcriptionally regulate the translation of their mRNA targets, and are therefore candidates mediating this control process. While the expression and importance of miRNAs in T and B lymphocytes has been established, little is known about miRNAs in NK cells. Here, we utilized two next-generation sequencing (NGS) platforms to define the miRNA transcriptomes of resting and cytokine-activated primary murine NK cells, with confirmation by RT-qPCR and microarrays. We delineate a bioinformatics analysis pipeline that identified 302 known and 28 novel mature miRNAs from sequences obtained from NK cell small RNA libraries. These miRNAs are expressed over a broad range, exhibit isomiR complexity, and a subset is differentially expressed following cytokine-activation. Using this miRNA NGS data, miR-223 was identified as a mature miRNA present in resting NK cells with decreased expression following cytokine-activation. Further, we demonstrate that miR-223 specifically targets the 3’UTR of murine GzmB in vitro, indicating that this miRNA may contribute to control of GzmB translation in resting NK cells. Thus, the sequenced NK cell miRNA transcriptome provides a valuable framework for further elucidation of miRNA expression and function in NK cell biology. Illumina GA (SRR036363, SRR036364) and SOLiD (SRR036206, SRR036210) sequencing data have been submitted to the NCBI Sequence Read Archive (SRA). The study uses a custome made array to characterize miRNA of activated and resting murine splenic natural killer cells
2010-10-01 | E-GEOD-21003 | biostudies-arrayexpress
Project description:Hydroxychloroquine inhibits trained immunity
| PRJNA670179 | ENA
Project description:We demonstrate that hydroxychloroquine inhibits trained immunity at the functional and epigenetic level and is accompanied by reduced expression of interferon-stimulated genes. Trained immunity comprises a functional adaptation induced by epigenetic reprogramming which facilitates the anti-viral innate immune response.
2020-10-21 | GSE159678 | GEO
Project description:scRNAseq of monocytes from in vitro Trained immunity experiments stimulated by β-glucan (BG), uric acid (UA), muramyl dipeptide (MDP), oxidized low-density lipoprotein (oxLDL), or RPMI-Control, and respective samples restimulated with Lipopolysaccharide (LPS).
2021-09-30 | E-MTAB-9702 | biostudies-arrayexpress
Project description:Natural killer (NK) cells are innate lymphocytes important for early host defense against infectious pathogens and surveillance against malignant transformation. Resting murine NK cells regulate the translation of effector molecule mRNAs (e.g. granzyme B, GzmB) through unclear molecular mechanisms. MicroRNAs (miRNAs) are small non-coding RNAs that post-transcriptionally regulate the translation of their mRNA targets, and are therefore candidates mediating this control process. While the expression and importance of miRNAs in T and B lymphocytes has been established, little is known about miRNAs in NK cells. Here, we utilized two next-generation sequencing (NGS) platforms to define the miRNA transcriptomes of resting and cytokine-activated primary murine NK cells, with confirmation by RT-qPCR and microarrays. We delineate a bioinformatics analysis pipeline that identified 302 known and 28 novel mature miRNAs from sequences obtained from NK cell small RNA libraries. These miRNAs are expressed over a broad range, exhibit isomiR complexity, and a subset is differentially expressed following cytokine-activation. Using this miRNA NGS data, miR-223 was identified as a mature miRNA present in resting NK cells with decreased expression following cytokine-activation. Further, we demonstrate that miR-223 specifically targets the 3’UTR of murine GzmB in vitro, indicating that this miRNA may contribute to control of GzmB translation in resting NK cells. Thus, the sequenced NK cell miRNA transcriptome provides a valuable framework for further elucidation of miRNA expression and function in NK cell biology. Illumina GA (SRR036363, SRR036364) and SOLiD (SRR036206, SRR036210) sequencing data have been submitted to the NCBI Sequence Read Archive (SRA).
2010-10-01 | GSE21003 | GEO
Project description:The maturation process determines NK cell functionality. We verified that tumor necrosis factor-alpha-induced protein-8 like-2 (TIPE2) works as a potent negative regulator in NK cell maturation. We found that TIPE2 expression gradually increased during NK cell ontogenesis correlating to their maturation stages in mice. NK-specific TIPE2 deficiency resulted in increased number of mature NK cells. To further confirm the role of TIPE2 in NK cell maturation, we performed single-cell RNA sequencing. Based on the key gene expression of NK cell effector molecules, transcriptional factors, maturation markers, and proliferation marker, we identified NK cell maturation program as Cluster#1->Cluster#2->Cluster#0 by which immature NK cells should go through to gain optimal effector functions at the cost of proliferation ability. According to this model, NK-specific TIPE2 deficient mice contained more NK cells belonging to the terminally mature Cluster#0 than control mice (up to 10% more), which is consistent with what we observed by flow cytometry. Therefore, these results collectively showed that NK-specific TIPE2 deficiency promotes NK cell maturation.
2021-09-22 | GSE168256 | GEO
Project description:The innate immune system plays an essential role in regulating the immune responses to kidney transplantation, but the mechanisms through which innate immune cells influence long-term graft survival are unclear. The current study highlights the vital role of trained immunity in kidney allograft survival. Trained immunity describes the epigenetic and metabolic changes that innate immune cells undergo following an initial stimulus, allowing them have a stronger inflammatory response to subsequent stimuli. We stimulated healthy peripheral blood mononuclear cells with pretransplant and posttransplant serum of kidney transplant patients and immunosuppressive drugs in an in vitro trained immunity assay and measured tumor necrosis factor and interleukin 6 cytokine levels in the supernatant as a readout for trained immunity. We show that the serum of kidney transplant recipients collected 1 week after transplantation can suppress trained immunity. Importantly, we found that kidney transplant recipients whose serum most strongly suppressed trained immunity rarely experienced graft loss. This suppressive effect of posttransplant serum is likely mediated by previously unreported effects of immunosuppressive drugs. Our findings provide mechanistic insights into the role of innate immunity in kidney allograft survival, uncovering trained immunity as a potential therapeutic target for improving graft survival.
2024-11-04 | GSE280787 | GEO
Project description:Trained immunity is a form of innate immune memory characterized by epigenetic and metabolic reprogramming in response to specific stimuli. This rewiring can result in increased cytokine and effector responses to pathogenic challenge, providing non-specific protection against disease. It may also improve immune responses to established immunotherapeutics and vaccines. Despite the promise of training for next-generation therapeutic design, most current understanding and experimentation is conducted with complex and heterogeneous biologically derived molecules, such as β-glucan or the BCG vaccine. This limited collection of training compounds also limits study of the genes most involved in training responses as each molecule has both training and non-training effects. Small molecules with tunable pharmacokinetics and delivery modalities would both assist in the study of trained immunity and its future application for therapeutics. To identify novel small molecule inducers of trained immunity, we screened a library of 2000 drugs and drug-like compounds. Identification of well-defined compounds can improve our understanding of innate immune memory and broaden the scope of its clinical applications. We identified over 2 dozen small molecules in several chemical classes, including the traditionally immunosuppressive glucocorticoids, that induce a training phenotype in the absence of initial immune activation – a current limitation of reported inducers of training. We chose 7 of these top candidates to characterize and establish training activity in vivo. In this work, we expand the number of compounds known to induce trained immunity, creating new avenues for the study and application of innate immune training.
2024-07-08 | GSE270608 | GEO