Similar Datasets
Project description:Innate lymphocytes in solid human tumors
| PRJNA863562 | ENA
Project description:γδ T lymphocytes represent ~1% of human PBMC and even more cells in most tissues of vertebrates. Although they have important anticancer functions, most current scRNA-Seq studies do not identify γδ T lymphocytes since their transcriptomes at the single cell level are unknown. Here we show that high resolution clustering of large scRNA-Seq data sets and a combination of gene signatures allow the specific detection of human γδ T lymphocytes and identification of their TCRVδ1 and TCRVδ2 subsets in large data sets from complex cell mixtures. In t-SNE plots from blood and tumor samples, the few γδ T lymphocytes appear collectively embedded between cytotoxic CD8 T and NK cells. Their TCRVδ1 and TCRVδ2 subsets form close yet distinct sub-clusters respectively neighbouring NK and CD8 T cells owing to expression of shared and distinct cytotoxic maturation genes. Similar pseudo-time maturation trajectories of TCRVδ1 and TCRVδ2 γδ T lymphocytes were discovered, unveiling in both subsets an unattended pool of TEMRA cells with preserved proliferative capacity, a finding confirmed by in vitro proliferation assays. Overall, the single cell transcriptomes of thousands of individual gd T lymphocytes from different CMV+ and CMV- donors reflect cytotoxic maturation stages driven by the immunological history of donors. This landmark study establishes the rationale for identification, subtyping and deep characterization of human γδ T lymphocytes in further scRNA-Seq studies of complex tissues in physiological and disease conditions.
2019-05-01 | GSE128223 | GEO
Project description:Natural Killer (NK) cells are innate lymphocytes capable of controlling tumors and virus infections through direct lysis and cytokine production. NK cells also expand and accumulate in affected tissues, but the role of NK cell expansion in tumor and viral control is not well understood. Here, we describe that post-transcriptional regulation by the RNA-binding protein HuR is essential for NK cell expansion, without overtly affecting NK cell effector functions. HuR-dependent NK cell expansion facilitated control of solid tumors, but it was dispensable for control of tumor metastases. In virus infection, HuR-dependent NK cell expansion contributed to long-term viral control in the absence of adaptive immunity without affecting acute infection. HuR-deficient NK cells displayed defects in expression of and splicing in cell cycle-associated genes, including decreased expression and alternative splicing of Ska2, a component of the spindle and kinetochore complex that is involved in chromosome separation during cell division. Furthermore, we identified an essential role for SKA2 in NK cell expansion. These results show that post-transcriptional regulation by HuR specifically affects NK cell expansion which is required for control of several solid tumors and long-term virus infection.
2023-08-31 | GSE217392 | GEO
Project description:The cytotoxic activity of lymphocytes is particularly dependent on the regulated and polarised delivery of lytic granules to infected or malignant cells. Although genetic and mechanistic studies have identified a number of factors that regulate exocytosis in cytotoxic lymphocytes, a systematic mapping of the relevant factors and their relationships is lacking. Here, using a genome-scale CRISPR knockout screen in human natural killer cells, we characterise a complex genetic network regulating cytotoxic granule exocytosis, with lipid metabolism and protein lipidation among the most prominent pathways. By combining global protein lipidation and membrane lipid composition studies, we further uncover the critical role of ZDHHC17 in SNAP23 palmitoylation and targeting of palmitoylated SNAP23 to the membrane for cytotoxic granule fusion and release. Using ODYA-17 labelling of Ctrl and sgZDHHC17 NK-92 cells followed by pulldown and proteomic analysis, we investigated the palmitoylome of the NK-92 model cell line. By comparing the abundance of ODYA-17 labelled proteins in the lysates of Ctrl and sgZDHHC17 NK-92 cells, we defined the molecules that depend on the activity of the palmitoyl transferase ZDHHC17.
2025-09-18 | PXD045419 | Pride
Project description:Innate lymphocytes encompass a diverse array of phenotypic identities with specialized effector functions. DNA methylation and hydroxymethylation are essential mechanisms for epigenetic fidelity and fate commitment. The landscapes of these modifications are unknown in innate lymphocytes. Here, we characterized the whole-genome distribution of methyl-CpG and 5-hydroxymethylcytosine (5hmC) in mouse ILC3, ILC2, and NK cells. We identified differentially methylated and hydroxymethylated DNA regions between ILC-NK subsets and correlated them with signature transcriptional modules. We associated lineage-determining transcription factors with demethylation and demonstrated unique patterns of DNA methylation/hydroxymethylation in relationship to open chromatin regions, histone modifications, and transcription factor binding sites. We also discover a novel association between 5hmC and NK cell super-enhancers. Using Tet2-deficient mice, we showed that the DNA hydroxymethylase Tet2 is required for optimal production of hallmark cytokines by ILC3 and production of IL-17A by inflammatory ILC2. These findings provide a powerful resource for studying immune epigenetic regulation and further decode the regulatory logic governing innate lymphocyte identity.
2022-02-16 | GSE190944 | GEO
Project description:We performed low input RNA-seq and single-cell RNA-seq to transcriptionally characterize four human innate T cell (ITCs) subsets, namely iNKT, MAIT, Vδ1 expressing γδ T cells, and Vδ2 expressing γδ T cells. We compared ITCs to CD4+ T and CD8+ T cells, representing the adaptive compartment, and to Natural Killer (NK) cells, representing the innate compartment.
2019-01-08 | GSE124731 | GEO
Project description:Intratumoral stimulatory dendritic cells (SDCs) play an important role in locally restimulating cytotoxic T cells and driving immune responses against cancer. However, the mechanisms that control SDC numbers remain poorly understood. In human melanoma, SDC numbers correlated with intratumoral expression of the gene encoding the cytokine FLT3LG, and we subsequently found in mouse and human tumors that this cytokine was predominantly produced by lymphocytes, notably including natural killer (NK) cells. NK cells stably formed conjugates with SDCs in the mouse tumor microenvironment (TME) and genetic and cellular ablation of NK cells in mice demonstrated their importance in regulation of SDC numbers through production of Flt3L. Although anti-PD-1 “checkpoint” immunotherapy for cancer largely targets T cells, we found that NK cells correlated with protective SDCs in human cancers, with patient responsiveness to anti-PD-1 immunotherapy, and with better overall survival. Our studies reveal that innate immune SDCs and NK cells cluster together as the best prognostic tool for T cell directed immunotherapy and that these innate cells are necessary for enhanced T cell tumor responses, suggesting this axis for novel therapies.
2018-04-14 | GSE113126 | GEO
Project description:The following lymphocytes were sorted from the lamin propria of the small intestine of EomesGfg/+ RORgtCreTGg Rosa26Yfp/+ by using the markers Lineage- CD45+ Nkp46+ NK1.1+ : 1.convential NK cells (Eomes GFP+ RORgt YFP-) 2. ILC1 (Eomes GFP- RORgt YFP-) 3. exRORgt ILC3 (Eomes GFP- RORgt YFP+). Conventional NK cells from the bone marrow (cNK BM) were sorted from Eomes Gfp/+ mice with the markers Lineage- CD45+ NK1.1+ Eomes GFP+.
2014-04-15 | E-MTAB-2428 | biostudies-arrayexpress
Project description:Intraepithelial lymphocytes expressing the gd T cell receptor (gd IEL) provide continuous surveillance of the intestinal epithelium. We report that mice harboring a microbiota-specific hyperproliferative gd IEL (gdHYP) phenotype also upregulate the expression of the ectonucleotidase CD39, a marker of regulatory gd T cells. Enhanced TCR and IL-15 signaling correlates with a progression from a naïve-like CD39neg gd IEL to a more mature, tissue-adapted CD39hi IEL population. We find that TCRgd activation drives CD122-mediated CD39 upregulation on gdHYP IELs and increased mucosal IL-15 further amplifies CD39 expression in gdHYP IELs. Notably, CD39 induction requires sustained exposure to the gdHYP-associated microbiota. Increased IL-15 signaling prolongs IEL survival and enhances gdHYP IEL bioenergetic potential. Notably, CD39hi gd IELs produce less pro-inflammatory cytokine, which may explain the lack of histopathology in gdHYP mice. Overall, our study identifies a previously unappreciated mechanism by which an altered microbiota amplifies CD39 expression on gdHYP IELs, leading to the expansion of gd IELs with regulatory potential.
2025-08-05 | GSE304526 | GEO
Project description:Intraepithelial lymphocytes expressing the gd T cell receptor (gd IEL) provide continuous surveillance of the intestinal epithelium. We report that mice harboring a microbiota-specific hyperproliferative gd IEL (gdHYP) phenotype also upregulate the expression of the ectonucleotidase CD39, a marker of regulatory gd T cells. Enhanced TCR and IL-15 signaling correlates with a progression from a naïve-like CD39neg gd IEL to a more mature, tissue-adapted CD39hi IEL population. We find that TCRgd activation drives CD122-mediated CD39 upregulation on gdHYP IELs and increased mucosal IL-15 further amplifies CD39 expression in gdHYP IELs. Notably, CD39 induction requires sustained exposure to the gdHYP-associated microbiota. Increased IL-15 signaling prolongs IEL survival and enhances gdHYP IEL bioenergetic potential. Notably, CD39hi gd IELs produce less pro-inflammatory cytokine, which may explain the lack of histopathology in gdHYP mice. Overall, our study identifies a previously unappreciated mechanism by which an altered microbiota amplifies CD39 expression on gdHYP IELs, leading to the expansion of gd IELs with regulatory potential.
2025-08-27 | GSE292555 | GEO