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Lupus susceptibility gene Esrrg regulates TREG development and suppressive function through mitochondrial metabolism

ABSTRACT: Lupus susceptibility gene Esrrg regulates TREG development and suppressive function through mitochondrial metabolism

PROVIDER: PRJNA631420 | ENA |

REPOSITORIES: ENA

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			Action	DRS
	SRR11744378.fastq.gz	Fastqsanger.gz
	SRR11744379.fastq.gz	Fastqsanger.gz
	SRR11744380.fastq.gz	Fastqsanger.gz
	SRR11744381.fastq.gz	Fastqsanger.gz
	SRR11744382.fastq.gz	Fastqsanger.gz

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Lupus susceptibility gene Esrrg regulates TREG development and suppressive function through mitochondrial metabolism

Project description:To investigate insight into how Esrrg regulates the TREG transcriptional program, we performed high-throughput RNA sequencing (RNA-seq) analysis of CD4+Foxp3-YFP+ from splenic cells of WT and KO female mice (2-3 months old). We show that the Esrrg-deficient Treg cells presented increased transcript related to oxidative phosphoration, cell cycle, proteasome, and antigen-presenting, suggesting Esrrg plays an essential role in mitochondral metabolism and it is associated with antigen-presenting and processing. Finally, Esrrg-deficient Treg displayed decreased Erbb and ribosome pathway, which may also related to TREG function. Our data suggest an critical role of lupus susceptibility gene Esrrg in regulating Treg cell function through mitochondrial metabolism.

2020-09-01 | GSE150187 | GEO

Transcriptional correlates of FOXP3 expression in suppressive and non-suppressive primary human Treg cell clones.

Project description:Analysis of the transcriptional correlates of FOXP3 expression in suppressive and non-suppressive primary human Treg cell clones. Individual CD4+CD25High or Cd4+CD25- T cells were isolated from human PBMCs and expanded in vitro. After 3 weeks of expansion, individual clones were analysed for FOXP3 expression and in vitro suppressive activity against freshly sorted allogeneic effector T cells. This study analyses the total RNA isolated from FOXP3+ clones with suppressive potency to their non-suppressive counterparts. The resutls of this study should provide insights into the molecular pathways linking FOXP3 expression to distinct aspects of Treg phenotype and function. Total RNA obtained from individual clones of primary human regulatory and effector CD4+T cells.

2015-05-06 | E-GEOD-65650 | biostudies-arrayexpress

Pre-B cell leukemia homeobox protein Pbx1 is associated with lupus susceptibility in mice and humans

Project description:Sle1a.1 is part of the Sle1a lupus susceptibility locus which results in the production of activated and autoreactive CD4+ T cells as well as a reduction in the peripheral regulatory T cell (Treg) pool. Sle1a.1 CD4+ T cells showed a defective response to retinoic acid (RA) expansion of TGFÎ²-induced Tregs. At the molecular level, Sle1a.1 corresponds to an increased expression of a novel splice isoform of Pbx1, Pbx1-d. Pbx1-d over-expression is sufficient to induce an activated/inflammatory phenotype in Jurkat T cells, and to decrease their apoptotic response to RA. PBX1-d is expressed more frequently in lupus patients than in healthy controls, and its presence correlates with an increased memory T cell population. These findings indicate that Pbx1 is a novel lupus susceptibility gene that regulates T cell activation and tolerance. Total RNA from CD4+ T cells from C57BL/6 (B6) and B6.Sle1a.1 (Sle) mice was isolated, with 4 biological replicates each. Gene expression data from C57BL/6 mice were compared with data from B6.Sle2c1 mice.

2010-07-08 | E-GEOD-22313 | biostudies-arrayexpress

Transcriptional correlates of FOXP3 expression in suppressive and non-suppressive primary human Treg cell clones.

2015-05-06 | GSE65650 | GEO

Mitochondrial integrity regulated by FABP5 is a cell-intrinsic checkpoint for Treg suppressive function

Project description:Regulatory T cells (Tregs) negatively regulate immune-mediated inflammation that is essential for preventing autoimmunity, but which can be detrimental in cancer. Central to Treg activation are changes in lipid metabolism to support their survival and function. Fatty acid binding proteins (FABPs) are a family of lipid chaperones required to facilitate the uptake and trafficking of intracellular lipids. One family member, FABP5, is expressed in certain T cell subsets, but its function remains elusive. We show here that in Tregs, FABP5 inhibition causes mitochondrial defects, underscored by decreased OXPHOS, lipid elongation and desaturation, and loss of cristae structure, which augment their suppressive function. Mitochondrial dysfunction after FABP5 inhibition results in mtDNA release and consequent cGAS/STING-dependent type I IFN signaling, which induces increased production of the regulatory cytokine IL-10, promoting Treg cell suppressive activity. Together these data reveal that FABP5 acts as a gatekeeper of mitochondrial health to control Treg cell function.

2019-12-26 | GSE126245 | GEO

Pre-B cell leukemia homeobox protein Pbx1 is associated with lupus susceptibility in mice and humans

Project description:Sle1a.1 is part of the Sle1a lupus susceptibility locus which results in the production of activated and autoreactive CD4+ T cells as well as a reduction in the peripheral regulatory T cell (Treg) pool. Sle1a.1 CD4+ T cells showed a defective response to retinoic acid (RA) expansion of TGFβ-induced Tregs. At the molecular level, Sle1a.1 corresponds to an increased expression of a novel splice isoform of Pbx1, Pbx1-d. Pbx1-d over-expression is sufficient to induce an activated/inflammatory phenotype in Jurkat T cells, and to decrease their apoptotic response to RA. PBX1-d is expressed more frequently in lupus patients than in healthy controls, and its presence correlates with an increased memory T cell population. These findings indicate that Pbx1 is a novel lupus susceptibility gene that regulates T cell activation and tolerance.

2010-06-16 | GSE22313 | GEO

MicroRNA profiling by PCR array of mouse Treg cells from non-autoimmune C3H/HeOuj and lupus prone MRL/lpr strains

Project description:Comparison of Treg miRNA expression between non-autoimmune C3H/HeOuj and lupus prone MRL/lpr mice

2011-11-30 | E-MEXP-2954 | biostudies-arrayexpress

mTOR coordinates transcriptional programs and mitochondrial metabolism of activated Treg subsets to protect tissue homeostasis

Project description:Regulatory T (Treg) cells derived from the thymus (tTreg) and periphery (pTreg) play central and distinct roles in immunosuppression, but mechanisms governing the generation and activation of Treg subsets in vivo remain uncertain. Here, we report that mechanistic target of rapamycin (mTOR) unexpectedly supports the homeostasis and functional activation of tTreg and pTreg cells. Further, mTOR signaling is crucial for programming activated Treg cell effector function to protect immune tolerance and tissue homeostasis. Treg-specific deletion of mTOR drives spontaneous TH2 responses and altered barrier tissue homeostasis, associated with reductions in both thymic derived effector Treg (eTreg) and pTreg cells. Mechanistically, mTOR acts downstream of antigenic signals to drive IRF4 expression and mitochondrial metabolism, and accordingly, disruption of mitochondrial metabolism severely impairs Treg cell suppressive function and their homeostasis in tissues. Collectively, our results demonstrate that mTOR coordinates transcriptional and metabolic programs in activated Treg subsets to mediate tissue homeostasis

2019-09-12 | GSE104130 | GEO

Lupus susceptibility loci predispose mice to clonal lymphocytic responses and myeloid expansion

Project description:Lupus susceptibility results from the combined effects of numerous genetic loci, but the contribution of these loci to disease pathogenesis has been difficult to study due to the large cellular heterogeneity of the autoimmune immune response. We performed single cell RNA, B cell receptor (BCR), and T cell receptor (TCR) sequencing of splenocytes from mice with multiple polymorphic lupus susceptibility loci. We not only observed lymphocyte and myeloid expansion, but also characterized changes in subset frequencies and gene expression, such as decreased CD8 and marginal zone B cells and increased Fcrl5 and Cd5l expressing macrophages. Clonotypic analyses revealed expansion of B and CD4 clones, and TCR repertoires from lupus prone mice were distinguishable by algorithmic specificity prediction and unsupervised machine learning classification. Myeloid differential gene expression, metabolism, and altered ligand-receptor interaction were associated with decreased antigen presentation. This dataset provides novel mechanistic insight into the pathophysiology of a spontaneous model of lupus, highlighting potential therapeutic targets for autoantibody mediated disease.

2022-03-14 | GSE192762 | GEO

Mitochondrial complex III is essential for regulatory T cell suppressive function. [DNA methylation/RRBS]

Project description:Regulatory T cells (Treg cells), a distinct subset of CD4+ T cells, are necessary for the maintenance of immune self-tolerance and homeostasis. Recent studies have demonstrated that Treg cells display a unique metabolic profile characterized by an increase in mitochondrial metabolism relative to other CD4+ effector subsets. Furthermore, the Treg cell lineage-defining transcription factor, Foxp3, has been shown to promote respiration; however, it remains unknown whether the mitochondrial respiratory chain is required for Treg cell suppressive capacity, stability, and survival. Here we report that Treg cell-specific ablation of mitochondrial respiratory chain complex III results in the development of a fatal inflammatory disease early in life, without impacting Treg cell number. Mice lacking complex III specifically in Treg cells displayed a loss of Treg cell suppressive capacity without altering Treg cell proliferation and survival. Treg cells deficient in complex III display decreased expression of genes associated with Treg function while maintaining stable FOXP3 expression. Complex III-null Treg cells displayed increased DNA methylation at the loci of differentially down-regulated genes without a global increase in DNA methylation. Loss of complex III in Treg cells resulted in buildup of the metabolites 2-hydroxyglutarate (2-HG) and succinate that can function as inhibitors of α-ketoglutarate (α−KG)-dependent dioxygenase reactions such as the ten-eleven translocation (TET) family of DNA demethylases. Thus, Treg cells require mitochondrial respiration to maintain immune regulatory gene expression and suppressive function.

2018-12-18 | GSE120451 | GEO

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