Lymphocyte activation gene 3 (Lag3) supports Foxp3+ Treg cell function by restraining c-Myc-dependent aerobic glycolysis
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PROVIDER: PRJNA938482 | ENA |
REPOSITORIES: ENA
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Project description:Lymphocyte activation gene 3 (Lag3) has emerged as the next-generation immune checkpoint molecule due to its ability to inhibit effector T cell activity. Foxp3+ regulatory T (Treg) cells, a master regulator of immunity and tolerance, also highly express Lag3. While Lag3 is thought to be necessary for Treg cell-mediated regulation of immunity, the precise roles and underlying mechanisms remain largely elusive. In this study, we report that Lag3 is indispensable for Treg cells to control autoimmune inflammation. Utilizing a newly generated Treg cell specific Lag3 mutant mouse model, we found that these animals are highly susceptible to autoimmune diseases, suggesting defective Treg cell function. Genome wide transcriptome analysis further uncovered that Lag3 mutant Treg cells upregulated genes involved in metabolic processes. Mechanistically, we found that Lag3 limits Treg cell expression of Myc, a key regulator of aerobic glycolysis. We further found that Lag3-dependent Myc expression determines Treg cells’ metabolic programming as well as the in vivo function to suppress autoimmune inflammation. Taken together, our results uncovered a novel function of Lag3 in supporting Treg cell suppressive function by regulating Myc-dependent metabolic programming.
2024-08-30 | GSE226083 | GEO
Project description:CD8+ T cell exhaustion is a distinct differentation state resulting from chronic antigen exposure and leading to hierarchical loss of effector functions. Using a murine model of diabetes, we show that CD8+ T cells derived from the islets of diabetic mice have CD8+ T cells that are canonically exhausted and yet retain sufficient effector function to contribute to pathogenicity in autoimmune diabetes. Genetic deletion of the inhibitory receptor LAG3 restricted to only CD8+ T cells lead to accelerated disease, with LAG3 deficient CD8+ T cells having enhanced effector function and trafficking. These findings reveal a distinct role of LAG3 in restraining autoreactive CD8+ T cells and implicate LAG3 as a potential therapeutic target in autoimmunity.
2022-04-08 | GSE199357 | GEO
Project description:1. The role of enhanced aerobic glycolysis in the transformation of rat thymocytes by concanavalin A has been investigated. Concanavalin A addition doubled [U-(14)C]glucose uptake by rat thymocytes over 3h and caused an equivalent increased incorporation into protein, lipids and RNA. A disproportionately large percentage of the extra glucose taken up was converted into lactate, but concanavalin A also caused a specific increase in pyruvate oxidation, leading to an increase in the percentage contribution of glucose to the respiratory fuel. 2. Acetoacetate metabolism, which was not affected by concanavalin A, strongly suppressed pyruvate oxidation in the presence of [U-(14)C]glucose, but did not prevent the concanavalin A-induced stimulation of this process. Glucose uptake was not affected by acetoacetate in the presence or absence of concanavalin A, but in each case acetoacetate increased the percentage of glucose uptake accounted for by lactate production. 3. [(3)H]Thymidine incorporation into DNA in concanavalin A-treated thymocyte cultures was sensitive to the glucose concentration in the medium in a biphasic manner. Very low concentrations of glucose (25mum) stimulated DNA synthesis half-maximally, but maximum [(3)H]thymidine incorporation was observed only when the glucose concentration was raised to 1mm. Lactate addition did not alter the sensitivity of [(3)H]-thymidine uptake to glucose, but inosine blocked the effect of added glucose and strongly inhibited DNA synthesis. 4. It is suggested that the major function of enhanced aerobic glycolysis in transforming lymphocytes is to maintain higher steady-state amounts of glycolytic intermediates to act as precursors for macromolecule synthesis.
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Project description:Comparison of gene expression profile of CD4+ CD25+, CD4+ CD25- CD45RBlow LAG3+ and CD4+ CD25- CD45RBlow LAG3- T cells. Naive CD4+CD25-CD45RBhigh T cells were used as a reference for pair comparison with values from the three other subsets.
2009-08-19 | E-MEXP-1343 | biostudies-arrayexpress
Project description:Transcriptonal analysis of Tregs reveal role of LAG3 in stability and function of Tregs in an inflamed CNS
2020-11-01 | GSE159342 | GEO
Project description:Immuno-LC-PRM assay was developed to simultaneously quantify the expression levels of six immune markers (CD8A, CD4, LAG3, PD1, PD-L1 and PD-L2) using as little as 1-2 mg of fresh frozen tissue.
2018-10-04 | PXD011152 | Pride
Project description:Mutations of the β-glucuronidase protein α-Klotho have been associated with premature aging, and altered cognitive function. Although highly expressed in specific areas of the brain, Klotho functions in the central nervous system remain unknow. Here, we show that cultured hippocampal neurons respond to insulin and glutamate stimulation by elevating Klotho protein levels. Conversely, AMPA and NMDA antagonism suppress neuronal Klotho expression. We also provide evidence that soluble Klotho enhances astrocytic aerobic glycolysis by hindering pyruvate metabolism through the mitochondria, and stimulating its processing by lactate dehydrogenase. Pharmacological inhibition of FGFR1, Erk phosphorylation, and monocarboxylic acid transporters prevents Klotho-induced lactate release from astrocytes. Taken together these data suggest Klotho is a potential new player in the metabolic coupling between neurons and astrocytes. Neuronal glutamatergic activity and insulin modulation elicit Klotho release, which in turn stimulates astrocytic lactate formation and release. Lactate can then be used by neurons as a metabolic substrate contributing to fulfill their elevated energy requirements.
2018-03-08 | GSE100046 | GEO
Project description:Increased high density lipoprotein (HDL) cholesterol levels have been associated with mutations in the cholesterol efflux receptor gene SCARB1, contributing to coronary artery disease (CAD). Using chromatin capture techniques (4C-Seq and HiC), ChIP-Seq and RNA-Seq, we identified a potential mechanism between a non-coding SNP (rs10846744) within the first intron of SCARB1 and LAG3, a negative regulator of T cells, both on chromosome 12. We previously demonstrated how loss of LAG3 is associated with inflammation and CAD found in carriers of the rs10846744 risk allele (C) both in our hyperalphalipoproteinemia (HALP) participants and the Multi-Ethnic Study of Atherosclerosis (MESA), increasing the risk of a coronary event by 45% (PMID: 27777974). NR2F2 transcription factor binding, as detected by (yeast 1 hybrid assay, ChIP, and ChIP-Seq) to the rs10846744 risk (C) allele, bridges NR2F2, SCARB1, and LAG3 loci, altering gene networks associated with a CAD proinflammatory signature. This SuperSeries is composed of the SubSeries listed below.
2019-10-04 | GSE110761 | GEO
Project description:The goal of this study was to apply Next Generation Sequencing analyses to identify genes and pathways regulated by the Foxp1 transcription factor in 3T3-L1 adipocytes. We found, that series of genes involved in metabolism, glycolysis, signal transduction, as well as nervous system development are regulated in response to overexpression and knock down of this transcription factor, thereby providing important insight into biological role of Foxp1 for cells survival and metabolism.
2023-05-05 | GSE179031 | GEO
Project description:Combined nivolumab (anti-PD1) and relatlimab (anti-LAG3) have shown enhanced effectiveness in melanoma patients. However, how these two receptors work together to hinder anti-tumor immunity remains unclear. Our study demonstrates that PD1/LAG3-deficient CD8+ T cells with more effectively clearing tumors and survive longer in melanoma mouse models. These PD1/LAG3-deficient CD8+ T cells have unique transcriptional profiles, broad TCR clonality, and enriched effector-like and interferon-responsive genes, leading to increased IFN gamma release indicating functionality. PD1 and LAG3 together drive T cell exhaustion, with a significant impact on TOX modulation. Mechanistically, autocrine IFN gamma signaling is crucial for enhancing anti-tumor immunity in PD1/LAG3-deficient CD8+ T cells, providing insights into the enhanced efficacy of combined PD1 and LAG3 targeting.
2024-08-07 | GSE262740 | GEO