Fat-to-blood recirculation of partially dysfunctional PD-1+CD4 Tconv cells is associated with dysglycemia in human obesity
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ABSTRACT:
PROVIDER: PRJNA994606 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR25269175.fastq.gz | Fastqsanger.gz | |||
| SRR25269175_1.fastq.gz | Fastqsanger.gz | |||
| SRR25269175_2.fastq.gz | Fastqsanger.gz | |||
| SRR25269176.fastq.gz | Fastqsanger.gz | |||
| SRR25269177.fastq.gz | Fastqsanger.gz |
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Project description:Obesity is characterized by accumulation of T cells in insulin-sensitive tissues, including the visceral adipose tissue (VAT), that can interfere with the insulin signaling pathway eventually leading to insulin resistance (IR) and type 2 diabetes. Here, we found that PD-1+CD4 conventional T (Tconv) cells, endowed with a transcriptomic and functional profile of partially dysfunctional cells, are diminished in VAT of obese patients with dysglycemia (OB-Dys). These cells showed enhanced capacity to recirculate into the bloodstream and had a non-restricted TCRβ repertoire divergent from that of normoglycemic obese and lean individuals. PD-1+CD4 Tconv were reduced in the circulation of OB-Dys, exhibited an altered migration potential, and were detected in the liver of patients with non-alcoholic steatohepatitis. The findings suggest that dysglycemia in individuals with obesity is associated with recirculation of a heterogeneous population of partially dysfunctional PD-1+CD4 Tconv cells. These changes may contribute to the inter-organ crosstalk underlying IR
2024-02-09 | GSE237338 | GEO
Project description:Fanconi–Bickel Syndrome (FBS) is a rare disorder of carbohydrate metabolism that is characterized by the accumulation of glycogen mainly in the liver. It is inherited in an autosomal recessive manner due to mutations in the SLC2A2 gene. SLC2A2 encodes for the glucose transporter GLUT2 and is expressed in tissues that are involved in glucose homeostasis. The molecular mechanisms of dysglycemia in FBS are still not clearly understood. In this study, we report two cases of FBS with classical phenotypes of FBS associated with dysglycemia. Genomic DNA was extracted and analyzed by whole-genome and Sanger sequencing, and patient PBMCs were used for molecular analysis. One patient had an exonic SLC2A2 mutation (c.1093C > T in exon 9, R365X), while the other patient had a novel intronic SLC2A2 mutation (c.613-7T>G). Surprisingly, the exonic mutation resulted in the overexpression of dysfunctional GLUT2, resulting in the dysregulated expression of other glucose transporters. The intronic mutation did not affect the coding sequence of GLUT2, its expression, or glucose transport activity. However, it was associated with the expression of miRNAs correlated with type 1 diabetes mellitus, with a particular significant overexpression of hsa-miR-29a-3p implicated in insulin production and secretion. Our findings suggest that SLC2A2 mutations cause dysglycemia in FBS either by a direct effect on GLUT2 expression and/or activity or, indirectly, by the dysregulated expression of miRNAs implicated in glucose homeostasis.
2022-09-28 | GSE198676 | GEO
Project description:Microarray used to detail the global gene transcription underlying sorted IFNg+ and IFNg- Tregs (CD4+CD25+CD127lo) and Tconv (CD4+CD25-CD127+) for fresh (unexpanded) and 14 day expanded cells from human blood. Treg and Tconv were FACS isolated from five healthy subjects (median age of 26, range 22-30). Sorted cells were separated into two groups: the first group was stimulated for 4 hours with PMA/ionomycin and labeled with the IFNg cytokine capture kit (Miltenyi Biotech) followed by FACS isolation of IFNg- and IFNg+ populations. The second set was expanded to day 14 prior to reactivation and cytokine cell capture. For each IFNg sorted population, cells were pelleted and flash frozen before RNA isolation and processing.
2015-05-01 | E-GEOD-59786 | biostudies-arrayexpress
Project description:miRNA expression profiling in highly purified murine CD4+ Tconv and Treg cells. FoxP3-GFP-hCre1a(high) reporter mice were used to separate both populations based on surface markers and presence or absence of GFP. Two-condition experiment, Tconv vs. Treg. Biological replicates: 1 Tconv, 1 Treg, purified from the same pooled mice. One replicate on 1 array.
2013-06-06 | E-GEOD-30847 | biostudies-arrayexpress
Project description:Microarray used to detail the global gene transcription underlying sorted IFNg+ and IFNg- Tregs (CD4+CD25+CD127lo) and Tconv (CD4+CD25-CD127+) for fresh (unexpanded) and 14 day expanded cells from human blood.
2015-05-01 | GSE59786 | GEO
Project description:We have employed whole genome microarray expression profiling of human Treg and Tconv cells as a discovery platform to identify genes differentially expressed upon signal of pseudostarvation (either mTOR inhibition or leptin neutralizaion) responsible for proliferation of Treg cell on one side and inhibition of Tconv cells on the other. Human Treg and Tconv cells isolated from healthy donors were pretreated or not with rapamycin or leptin mAb and stimulated with anti-CD3 and anti-CD28 beads for 12h.
2021-05-17 | GSE154401 | GEO
Project description:Since the intronic mutation in SLC2A2 did not influence the activity of GLUT2, we undertook more investigation to understand the underlying molecular mechanisms of dysglycemia in FBS. We ran Nanostring miRNA panel v3b covering ~800 miRNAs in the patient, mother, and aged- and gender-matching healthy controls with no family history of dysglycemia. We noticed a higher degree of correlation between the patient and the gender and age-matched healthy control, rather than between the patient and the mother, suggesting that the miRNA expression profile might be more influenced by the age and gender rather than relatedness (Supplementary Fig. S5). The unsupervised hierarchical clustering revealed 123 miRs expressed specifically in the patient sample (Supplementary Table S2). The function of these miRNAs was interrogated by using Ingenuity Pathway (IPA) analysis software which returned 118 mapped miRs (Fig. 10). Here we report 30 miRNAs with the highest number of counts difference in the patient in comparison to controls (Fig. 11). We found that 14 of them were correlated with T1DM: 10 miRNAs (miR-199a, miR-25-3p, miR-93-5p, miR-19b-3p, miR-107, miR-24-3p. miR-18a-5p, miR-125b-5p, miR-324-5p, miR-331-3p, and hsa-miR-143-3p) were overexpressed in the control as compared to the patient, and 3 miRNAs (miR-144-3p , let-7e-5p, hsa-miR-29a-3p) were significantly overexpressed in the patient in comparison to the control. Molecular networks, including molecules inferred from previous studies, were generated by IPA functional analysis software (Supplementary Fig. S6). The molecular networks were given a score based on the number of molecules represented in the study dataset as compared to the literature. Network 1 (score 33) includes the genes and miRNAs implicated in organismal injury and abnormalities, skeletal and muscular system development and function, and tissue morphology. The miR-144 family integrated into the network 1. Network 2 (score 31) includes insulin and other genes and miRNAs implicated in glomerular injury, inflammatory disease, inflammatory response, and included miR-29 and let-7 families. These results suggest that dysglycemia in the patient with intronic mutation might be associated with the deregulation of miRNAs involved in insulin production and secretion in beta cells.
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Project description:Single cell VDJ and RNAseq of Tconv and Treg cells obtained from BALB/c FoxP3-GFP reporter mice
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Project description:MicroRNAs (miRNAs) are small non-coding molecules targeting messenger RNAs and inhibiting protein translation. Regulated by dynamic micro-environmental cues, miRNAs in turn modulate key biological processes, including cell growth and development, energy utilization and homeostasis. In particular, miRNAs control the differentiation, survival and activation of CD4+ T conventional (Tconv) cells, key players of the adaptive immunity and miRNA-mediated gene expression regulation contributes to the physiological response to infections and the pathological loss of immune homeostasis in autoimmunity. Upon T cell receptor (TCR) stimulation, the described global miRNA quantitative decrease occurring in T cells is believed to promote the acquisition of effector functions by relaxing the post-transcriptional repression of genes associated to proliferation and cell activity. While miRNAs were initially thought to get down-regulated uniquely by intracellular degradation, miRNA secretion via extracellular vesicles (EVs) represents an additional mechanism of rapid down-regulation. By focusing on molecular interactions by means of graph theory, we have found that miRNAs released by TCR stimulated Tconv cells are significantly enriched for targeting transcripts up-regulated upon stimulation, including those encoding for crucial proteins associated to Tconv cell activation and function. Based on this computational approach, we present our perspective based on the following hypothesis: a stimulated Tconv cell will release miRNAs targeting genes associated to the effector function in the extracellular space in association with EVs, which will thus possess a suppressive potential toward other Tconv cells in the paracrine environment. We also propose possible future directions of investigation aimed at taking advantage of these phenomena to control Tconv cell effector function in health and autoimmunity.
2021-10-31 | GSE183713 | GEO
Project description:Social overcrowding impacts gut microbiota, promoting stress, inflammation and dysglycemia
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