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Global expression profile of spleen DNAM-1+ and DNAM-1- NK cells.

ABSTRACT: We determined the global expression profile of DNAM-1+ and DNAM-1- NK cell purified by flow cytometry from 6 different groups of C57BL/6 WT mice. Natural killer (NK) cells comprise a heterogeneous population of cells important for pathogen defense and cancer surveillance. However, the functional significance of this diversity is not fully understood. Here, we demonstrate through transcriptional profiling and functional studies that the activating receptor DNAM-1 (CD226) identifies two distinct NK cell functional subsets: DNAM-1+ and DNAM-1- NK cells. DNAM-1+ NK cells have enhanced Interleukin 15 signaling, proliferate vigorously and produce high levels of inflammatory cytokines. By contrast, DNAM-1- NK cells that differentiate from DNAM-1+ NK cells, have greater expression of NK cell receptor related genes and are higher producers of chemokines. Together our findings highlight the existence of two distinct effector programs in innate lymphocytes controlled through DNAM-1 expression.

ORGANISM(S): Mus musculus

PROVIDER: GSE66281 | GEO | 2015/02/26

SECONDARY ACCESSION(S): PRJNA276407

REPOSITORIES: GEO

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Global expression profile of spleen DNAM-1+ and DNAM-1- NK cells.

Project description:We determined the global expression profile of DNAM-1+ and DNAM-1- NK cell purified by flow cytometry from 6 different groups of C57BL/6 WT mice. Natural killer (NK) cells comprise a heterogeneous population of cells important for pathogen defense and cancer surveillance. However, the functional significance of this diversity is not fully understood. Here, we demonstrate through transcriptional profiling and functional studies that the activating receptor DNAM-1 (CD226) identifies two distinct NK cell functional subsets: DNAM-1+ and DNAM-1- NK cells. DNAM-1+ NK cells have enhanced Interleukin 15 signaling, proliferate vigorously and produce high levels of inflammatory cytokines. By contrast, DNAM-1- NK cells that differentiate from DNAM-1+ NK cells, have greater expression of NK cell receptor related genes and are higher producers of chemokines. Together our findings highlight the existence of two distinct effector programs in innate lymphocytes controlled through DNAM-1 expression. NK1.1+NKp46+CD3- DNAM-1+ and DNAM-1- NK cell were purified by flow cytometry from 6 different groups of C57BL/6 WT mice and total RNA were extracted

2015-02-26 | E-GEOD-66281 | biostudies-arrayexpress

Next-generation sequencing facilitates quantitative analysis of DNAM-1+ and DNAM-1- natural killer (NK) cells transcriptomes in mouse MLL-AF9 AML leukemia

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Transcriptomic analysis of freshly purified human CD226- and CD226+ CD8+ T cell subsets isolated from the peripheral blood of healthy donors.

Project description:We recently found that loss of the activating receptor CD226 (DNAM-1) was a critical mechanism affecting CD8+ T cell responsiveness to TCR stimulation. To better understand the molecular differences between CD226- and CD226+ CD8+ T cells, we decided to perform a global transcriptional analysis of purified naive (Tn, CD62L+CD45RA+), central memory (Tcm, CD62L+CD45RA-) and terminal effector memory (Temra, CD62L-CD45RA+) CD226+ and CD226- CD8+ T cells using next generation RNA sequencing.

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The emergence of DNAM-1 as the facilitator of NK cell-mediated killing in Ovarian Cancer

Project description:Ovarian cancer (OC) is the sixth most common malignancy in women and the poor 5-year survival emphasises the need for novel therapies. NK cells play an important role in the control of malignant disease but the nature of tumour-infiltrating and peripheral NK cells in OC remains unclear. We studied the phenotype and function of NK cells in blood, primary tumour and metastatic tissue in 80 women with OC. The proportion of peripheral NK cells was markedly elevated with a highly activated profile and increased cytotoxicity. In contrast, NK cell numbers in primary tumour and metastasis were substantially reduced, with downregulation of activatory receptors together with elevated PD-1 expression. scRNA-Seq identified 5 NK cell subpopulations along with increased exhausted and immature NK cells within tumour tissue compared to normal tissue. These features were attenuated following chemotherapy where higher levels of activated and cytotoxic NK cells associated with improved disease-free survival. Correlation of NK cell phenotype with clinical outcomes revealed high levels of DNAM-1 expression on tissue-localised and peripheral NK cells to be associated with reduced survival. Expression of PVR, the DNAM-1 ligand, was significantly increased on tumours and DNAM-1 mediated NK cell lysis of primary tumour tissue was observed in vitro. These findings reveal profound modulation of the tumour tissue and systemic profile of NK cells which likely contributes to the high rates of local progression and metastasis seen with OC. Immunotherapeutic approaches that overcome local immune suppression and enhance DNAM-1-targeted lysis of OC offer the potential to improve disease control.

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Transcriptomic analysis of resting or activated human CD226- and CD226+ effector memory CD8+ T cell subsets isolated from the peripheral blood of healthy donors.

Project description:We recently found that loss of the activating receptor CD226 (DNAM-1) was a critical mechanism affecting CD8+ T cell responsiveness to TCR stimulation. To better understand the molecular differences between CD226- and CD226+ CD8+ T cells, we decided to perform a global transcriptional analysis of purified CD226+ and CD226- CD8+ effector memory T cells before and after TCR activation using next generation RNA sequencing. We report here the total RNA sequencing of healthy donor resting CD226- and CD226+ CD8+ Tem cells (n=6/group) or activated (ACT, n=4/group) by α-CD2/CD3/CD28 for 24 hrs.

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Gene expression profiling of NKG2C+ NK cells generated from inflammatory CD34+DNAM-1brCXCR4+ and Lin-CD34- CD16+CD56- blood precursors

Project description:There is limited knowledge on the origin and development of the ample spectrum of human NK cells, particularly of specialized NK subsets. Here, we characterized the NK cell progeny of CD34+DNAM-1bright CXCR4+ precursors that reside in healthy bone marrow and circulate in the peripheral blood (PB) of patients with chronic infections/inflammation. including HIV, HCV or HCMV reactivation after HSC transplantation. Unlike conventional CD34+ precursors they rapidly differentiated in vitro into cytotoxic, IFNγ-secreting CD94/NKG2C+KIR+CD57+ maturing NK cell progenies with HCMV-inhibiting activity. Progeny characterization led also to identification of an additional new PB Lin-CD56-CD16+ precursor giving rise to the same CD94/NKG2C+KIR+CD57+ maturing NK cell progenies. Microarray analysis of NK cell progenies revealed a signature compatible with maturing adaptive NK cells. In vivo circulation of multiple common lymphocyte precursors with rapid development to NKG2C+ NK cell progeny is steadily occurring and may thus be a crucial resource for the prompt control of HCMV. We used microarray to compare the transcriptional profiles of human NKG2C+ NK cells derived from i) CD34+DNAM1brightCXCR4+ precursors, ii) Lin-CD34-CD16+CD56- precursors, iii) peripheral blood.

2020-12-31 | GSE136570 | GEO

RNA-seq of CD226-overexpressing NK cells and CD226-overexpressing nduced pluripotent stem cell-derived NK cells(iPSC-NK)

Project description:RNA-seq of CD226-overexpressing NK cells and CD226-overexpressing nduced pluripotent stem cell-derived NK cells(iPSC-NK)

| PRJNA1237813 | ENA

CD34+DNAMbrightCXCR4+ CLP mobilized in chronic inflammation

Project description:During the course of many chronic inflammatory disorders, a persistent Natural Killer (NK) cell derangement and activation is observed. While increased cell turnover is expected in these cases, little is known about whether and how NK cell homeostatic balance and numbers are maintained by CD34+ progenitor cells. Accordingly, we studied peripheral blood progenitor cells in patients with chronic inflammatory disorders including HIV-1, HCV, TB, COPD and PAPA. Cytometric analysis revealed the presence of a so far unidentified CD34+CD226(DNAM-1)brightCXCR4+ cell population in all these conditions. Further, microarray and PCR analysis showed transcriptional signatures typical of common lymphocyte precursors. Culture of CD34+CD226brightCXCR4+ cells gave rise to NK cell progenies characterized by high expression of activating receptors and mature function. Importantly, in healthy donors CD34+CD226brightCXCR4+ cells reside in bone marrow but do not circulate in peripheral blood and are absent in umbilical cord blood. The proportion of CD34+CD226brightCXCR4+ PBMC were found to correlate with the degree of inflammation, and represent an indicator of lymphoid cell turnover/reconstitution during chronic inflammation. Identification of CD34+CD226brightCXCR4+ circulation offers a novel view of emergency recruitment of cell-precursors upgrade our understanding and monitoring of chronic inflammatory conditions, and provide new insight of intermediate stages of NK cell development. Four samples from CD34+ hematopoietic stem cells of healthy individuals (n=2) and HIV-infected patients (n=2) were analyzed using GeneChip Human Gene 1.0 ST Arrays.

2015-07-01 | E-GEOD-69557 | biostudies-arrayexpress

Matrix Elasticity Does Not Affect Replicative Senescence or DNA Methylation Patterns of Mesenchymal Stem Cells [DNAm profiling]

Project description:Matrix elasticity influences differentiation of mesenchymal stem cells (MSCs) but it is unclear if these effects are only transient - while the cells reside on the substrate - or if they reflect persistent lineage commitment. In this study, MSCs were continuously culture-expanded in parallel either on polydimethylsiloxane (PDMS) gels of different elasticity or on tissue culture plastic (TCP) to compare impact on replicative senescence, in vitro differentiation, gene expression, and DNA methylation (DNAm) profiles. The maximal number of cumulative population doublings was not affected by matrix elasticity. Differentiation towards adipogenic and osteogenic lineage was increased on soft and rigid biomaterials, respectively - but this propensity was no more evident if cells were transferred to TCP. Global gene expression profiles and DNAm profiles revealed relatively few differences in MSCs cultured on soft or rigid matrices. Furthermore, only moderate DNAm changes were observed upon culture on very soft hydrogels of human platelet lysate (hPL-gel). Our results support the notion that matrix elasticity influences cellular differentiation while the cells are organized on the substrate, but it does not have major impact on cell-intrinsic lineage determination, replicative senescence or DNAm patterns. 20 samples were hybridized to the Illumina Infinium 450k Human Methylation Beadchip

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