Hexokinase 2 is dispensable for T cell-dependent immunity
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ABSTRACT:
PROVIDER: PRJNA485187 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR7661960.fastq.gz | Fastqsanger.gz | |||
| SRR7661970.fastq.gz | Fastqsanger.gz | |||
| SRR7661961.fastq.gz | Fastqsanger.gz | |||
| SRR7661971.fastq.gz | Fastqsanger.gz | |||
| SRR7661962.fastq.gz | Fastqsanger.gz |
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Project description:Hexokinase 2 (HK2) is one the most highly upregulated enzymes in glycolysis in activated T cells and cancer cells. We genetically abolished HK2 expression in T cells in vivo and infected mice with LCMV to induce T cell proliferation. CD8+ T cells from were sorted from spleens of WT and HK2 null mice 8 days after infection. Additionally, WT CD8+ T cells were compared to WT primary T cell acute lymphoblastic leukemia (T-ALL). T-ALL cells were sorted from spleens of mice 6 weeks after adoptive transfer of bone marrow that overexpresses mutant Notch1 (Notch1-deltaE).
2018-08-13 | GSE118326 | GEO
Project description:Background:T cells and cancer cells utilize glycolysis for proliferation. The hexokinase (1-4) family of enzymes catalyze the first step of glycolysis. Hexokinase 2 (HK2) is one of the most highly upregulated metabolic enzymes in both cancer and activated T cells. HK2 is required for the development and/or growth of cancer in several cancer models, but the necessity of HK2 in T cells is not fully understood. The clinical applicability of HK2 inhibition in cancer may be significantly limited by any potential negative effects of HK2 inhibition on T cells. Therefore, we investigated the necessity of HK2 for T cell function. In order to identify additional therapeutic cancer targets, we performed RNA-seq to compare in vivo proliferating T cells to T cell leukemia. Methods:HK2 was genetically ablated in mouse T cells using a floxed Hk2 allele crossed to CD4-Cre. CD4+ and CD8+ cells from mice were characterized metabolically and tested in vitro. T cell function in vivo was tested in a mouse model of colitis, Th2-mediated lung inflammation, and viral infection. Treg function was tested by crossing Hk2-floxed mice to FoxP3-Cre mice. Hematopoietic function was tested by deleting HK2 from bone marrow with Vav1-iCre. RNA-seq was used to compare T cells proliferating in response to virus with primary T-ALL leukemia induced with mutant Notch1 expression. Results:We unexpectedly report that HK2 is largely dispensable for in vitro T cell activation, proliferation, and differentiation. Loss of HK2 does not impair in vivo viral immunity and causes only a small impairment in the development of pathological inflammation. HK2 is not required for Treg function or hematopoiesis in vivo. One hundred sixty-seven metabolic genes were identified as being differentially expressed between T cells and leukemia. Conclusions:HK2 is a highly upregulated enzyme in cancer and in T cells. The requirement for HK2 in various cancer models has been described previously. Our finding that T cells are able to withstand the loss of HK2 indicates that HK2 may be a promising candidate for cancer therapy. Furthermore, we identify several other potential metabolic targets in T-ALL leukemia that could spare T cell function.
| S-EPMC6098591 | biostudies-literature
Project description:cIAP1/2 antagonism induces antigen-specific T cell dependent immunity
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Project description:The coordinated release of proteins by T cells enables controlled biological responses. While the molecular mechanisms underlying T cell secretion are being increasingly understood, whether the critical ER-to-Golgi trafficking pathway regulates T cell immunity is not known. We utilized mice with a T cell-specific deletion of SEC23B, a core subunit of Coat Protein Complex II (COPII) which drives ER-to-Golgi cargo transport. We found that following activation, SEC23B-deficient T cells display an altered secretome compared to wild-type, which includes reduced secretion of T cell-derived inflammatory mediators, and which is associated with functional ramifications in vitro and in vivo. Together, these data reveal a critical role for the SEC23B-dependent COPII pathway in T cell immunity.
2021-09-08 | PXD015766 | Pride
Project description:A hexokinase isoenzyme switch in human liver cancer cells promotes lipogenesis and enhances innate immunity
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Project description:Hexokinase 3 enhances myeloid cell survival via non-glycolytic functions
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Project description:Multispecies STING-dependent antiviral immunity
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Project description:Host immunity limits iron availability to pathogenic bacteria, but whether immunity limits pathogenic bacteria from accessing host heme, the major source of iron in the body, remains unclear. Using Citrobacter rodentium, a mouse enteric pathogen and Escherichia coli, a major cause of sepsis in humans as models, we find that interleukin-22, a cytokine best known for its ability to promote epithelial barrier function, also suppresses the systemic growth of bacteria by limiting iron availability to the pathogen. Using an unbiased proteomic approach to understand the mechanistic basis of IL-22 dependent iron retention in the host, we have identified that IL-22 induces the production of the plasma hemoglobin scavenger haptoglobin and heme scavenger hemopexin. Moreover, the anti-microbial effect of IL-22 depends on the induction of hemopexin expression, while haptogloblin is dispensable. Impaired pathogen clearance in infected Il22-/- mice was restored by hemopexin administration and hemopexin-deficient mice had increased pathogen loads after infection. These studies reveal a previously unrecognized host defense mechanism regulated by IL-22 that relies on the induction of hemopexin to limit heme availability to bacteria leading to suppression of bacterial growth during systemic infections.
2017-02-03 | PXD005666 | Pride
Project description:It has been strongly argued that plant cells should have a means of sensing sugars at the cell surface, so that extracellular and intracellular sugars can be sensed separately and their metabolism coordinated (Lalonde et al., Plant Cell, 11, 707-26, 2000). There is good evidence for an intracellular hexokinase-dependent pathway of hexose sensing in plants, but very little evidence for a hexokinase-independent signalling pathway, such as that provided by SNF3 or RGT2 in yeast. Many papers on sugar sensing in plants cite work from two laboratories as evidence for hexokinase-independent hexose signalling in plants. The first is that in which cell-wall invertase and sucrose synthase genes were induced by treatment of a Chenopodium suspension culture with 30 mM 6-Deoxyglucose (6DOG) for 24 h (Roitsch et al., Plant Physiol 108, 285-294, 1995; Godt et al., J. Plant Physiol 146, 231-238, 1995). The second is that in which a patatin transgene in Arabidopsis was shown to be weakly induced by growth over several days on a mixture of 30 mM glucose plus 30 mM 3-O-methylglucose (3OMG), but strongly induced by growth on 30 mM Glc plus 90 mM 3OMG (Martin et al., Plant J, 11, 53-62, 1997). We are not aware of any examples of Arabidopsis genes which respond to 6DOG or 3OMG yet this is an area of wide significance. Identification of such a gene would help to establish if a hexokinase-independent signalling system operates in plants, and would provide a basis for establishment of a genetic screen for mutants, using the gene promoter linked to a reporter such as luciferase. The aim of this proposal is to discover any genes which are either activated or repressed by glucose AND by 3OMG and/or 6DOG, but not by mannitol (an osmotic control). The use of both 3OMG and 6DOG will help to identify non-specific effects of either. All substrates will first be analysed by HPLC to confirm that they are pure. Arabidopsis Col-0 seedlings will be grown in vitro for 7 days in the absence of sugars, then treated with 30 mM glucose or glucose analogue for 8 h (these conditions are based on concentrations and time courses of Roitsch et al.). RNA will then be isolated from multiple independent plates to minimise biological variation. Experimenter name = Dorthe Villadsen; Experimenter phone = 0131 650 5318; Experimenter fax = 0131 650 5392; Experimenter address = Institute of Cell and Molecular Biology; Experimenter address = University of Edinburgh; Experimenter address = The King_s Buildings; Experimenter address = Mayfield Road; Experimenter address = Edinburgh; Experimenter zip/postal_code = EH9 3JH; Experimenter country = UK Experiment Overall Design: 6 samples were used in this experiment
2008-06-14 | E-GEOD-5723 | biostudies-arrayexpress