Endogenous expression of CD83 in Foxp3+ T cells essentially contributes to differentiation and function of murine Foxp3+ effector regulatory T cells
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA417322 | ENA |
REPOSITORIES: ENA
Similar Datasets
Project description:Foxp3-positive regulatory T (Treg) cells are crucial players for the maintenance of immune homeostasis and keep immune responses in check. Upon activation, Treg are transferred into an effector state expressing transcripts essential for their suppressive activity, migration and survival. However, how different intrinsic and environmental factors control differentiation is still not completely understood. Here, we present for the first time data suggesting that Treg intrinsic expression of CD83 is essential for Treg differentiation upon activation. Interestingly, mice with Treg intrinsic CD83 deficiency are characterized by a pro-inflammatory phenotype. Furthermore, the loss of CD83 expression by Treg leads to the downregulation of Treg specific differentiation markers and the induction of an inflammatory profile. In addition, Treg specific conditional knockout mice showed aggravated autoimmunity and an impaired resolution of inflammation. Altogether, CD83 expression in Treg cells is an essential factor for the development and function of effector Treg cells upon activation.
2020-03-31 | GSE106598 | GEO
Project description:Microglial activation during neuroinflammation is crucial for coordinating the immune response against neuronal tissue and the initial response of microglia determines the severity of neuroinflammatory diseases. CD83 has been associated with early activation of microglia in various disease settings albeit its functional relevance for microglial biology was still elusive. Thus, we conducted a thorough assessment of CD83 regulation in microglia as well as its impact on microglial mediated neuroinflammation. Here, we describe for the first time that CD83 expression in microglia is not only associated with cellular activation but also with pro-resolving functions. Conditional deletion of CD83 causes malfunctioning responses to myelin debris, which results in an over-activated state during autoimmune neuroinflammation. Subsequently, CD83-deficient microglia recruit more pathogenic immune cells to the central nervous system and deteriorate resolving mechanism, which exacerbates the disease. Thus, CD83 in microglia orchestrates cellular activation and consequently, also resolution of neuroinflammation.
2023-06-28 | GSE230753 | GEO
Project description:We performed RNA-Seq of CD83 overexpression SKOV3 cells (OV_1, OV_2, OV_3), CD83 knockdown SKOV3 cells (KD_1, KD_2, KD-3), and control SKOV3 cells (NC_1, NC_2, NC_3) using BGISEQ-500 platform (BGI, China).
2019-01-14 | GSE125011 | GEO
Project description:This study aims to characterize the transcriptome in wild type and Gls B KO CD83+ly75+GCB cells, and find the potential mechanism of the Gls B KO CD83+ly75+GCB cells。
2026-01-12 | GSE285673 | GEO
Project description:Regulatory T (Treg) cells maintain immune tolerance through the action of the master regulator FOXP3, a transcription factor crucial for Treg cells function and homeostasis. We identified an IPEX patient with a FOXP3 mutation in the domain swap interface of the protein (mutant M370I). Recapitulation of this Foxp3 variant in mice led to an autoimmune syndrome similar to the patient and consistent with an unrestrained Th2 immune response. Genomic analysis of Treg cells by RNA-seq, Foxp3 ChIP-seq and H3K27ac-HiChIP revealed a specific de-repression of the T helper type 2 (Th2) transcriptional program leading to the generation of Th2-like Treg cells that are unable to suppress extrinsic Th2 cells. Th2-like Treg cells are characterized by increased intra-chromosomal interactions in the Th2 locus leading to type-2 cytokines production. Our research provides cellular and molecular characterizations of mechanisms used by Foxp3 to restrain Th2 transdifferentiation and promote optimal Treg suppressive function and stability.
2018-12-31 | GSE112176 | GEO
Project description:Studies of the monogenic autoimmune disease immunodysregulation polyendocrinopathy enteropathy X-linked syndrome (IPEX) have elucidated the essential function of the transcription factor FOXP3 and thymic-derived regulatory T cells (Tregs) in controlling peripheral tolerance. However, the presence and the source of autoreactive T cells in IPEX remain undetermined. Here, we investigated how FOXP3 deficiency affects the T cell receptor (TCR) repertoire and Treg stability in vivo and compared T cell abnormalities in patients with IPEX to those in patients with autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy syndrome (APECED). To study Tregs independently of their phenotype and to analyze T cell autoreactivity, we combined Treg-specific demethylation region analyses, single-cell multi-omic profiling, and bulk TCR sequencing. We found that patients with IPEX, unlike patients with APECED, have expanded autoreactive T cells originating from both autoreactive effector T cells (Teffs) and Tregs. In addition, a fraction of the expanded Tregs lost their phenotypic and functional markers including CD25 and often also FOXP3. Functional experiments with CRISPR/Cas9-mediated FOXP3 knock-out Treg and Tregs from patients with IPEX indicated that the patients’ Tregs gain a Th2 skewed Teff-like function, which is consistent with immune dysregulation observed in these patients. Analyses of FOXP3 mutation-carrier mothers and a patient with IPEX after hematopoietic stem cell transplantation, indicated that Tregs expressing non-mutated FOXP3 prevent the accumulation of autoreactive Teffs and unstable Tregs. Collectively, we describe Treg instability and Teff autoreactivity in patients with IPEX. These findings could be directly used for diagnostic and prognostic purposes and for monitoring the effects of immunomodulatory treatments.
2023-12-20 | GSE247274 | GEO
Project description:CD4+ regulatory T cells (Tregs) are key mediators of immunological tolerance and promising effector cells for immuno-suppressive adoptive cellular therapy to fight autoimmunity and chronic inflammation. Their functional stability is critical for their clinical utility and has been correlated to the demethylated state of the TSDR/CNS2 enhancer element in the Treg lineage transcription factor FOXP3. However, proof for a causal contribution of the TSDR de-methylation to FOXP3 stability and Treg induction is so far lacking. We here established a powerful transient-transfection CRISPR-Cas9-based epigenetic-editing method for the selective de-methylation of the TSDR within the endogenous chromatin environment of a living cell. The induced de-methylated state was stable over weeks in clonal T cell proliferation cultures even after expression of the editing complex had ceased. Epigenetic editing of the TSDR resulted in FOXP3 expression, even in its physiological isoform distribution, proving a causal role for the de-methylated TSDR in FOXP3 regulation. However, successful FOXP3 induction was not associated with a switch towards a functional Treg phenotype, in contrast to what has been reported from FOXP3 overexpression approaches. Thus, TSDR de-methylation is required, but not sufficient for a stable Treg phenotype induction. Therefore, targeted demethylation of the TSDR may be a critical addition to published in vitro Treg induction protocols which so far lack FOXP3 stability.
| EGAS00001004867 | EGA
Project description:Regulatory T cells have been shown to adopt a catabolic metabolic programme with increased capacity for fatty acid oxidation fuelled oxidative phosphorylation (OXPHOS). The role of Foxp3 in this metabolic shift is poorly understood. Here we show that Foxp3 was sufficient to induce a significant increase in the spare respiratory capacity of the cell, the extra OXPHOS capacity available to a cell to increased demands on energy in response to work. Foxp3-expressing cells were enhanced in their ability to utilise palmitate for respiration and in addition the activity of electron transport complexes I, II and IV were enhanced following Foxp3 expression. ATP was secreted by both T effector and regulatory T cells and was reduced by mitochondrial respiration inhibitors. Thus Foxp3 imparts a selective advantage in ATP generation capacity to the cell and may exploit this as a source of adenosine for functional immunomodulation. In order to explore possible mechanisms for these differences in metabolism we conducted a comparative quantitative proteomics study to compare the contribution of TGFβ and the transcription factor Foxp3 to the Treg proteome. We used quantitative mass spectrometry to examine differences between proteomes of nuclear and cytoplasmic Foxp3-containing T cells and Foxp3 positive iTreg and Foxp3 negative activated CD4 T cells in addition to human peripheral blood natural Treg. Gene set enrichment analysis of our proteomic datasets demonstrated that Foxp3 drives a significant up regulation of several members of the mitochondrial electron transport chain.
2017-02-15 | PXD001789 | Pride
Project description:Analysis of Foxp3(+)epigenetics(-) T cells, Foxp3(-)epigenetics(+) T cells, and Foxp3(+)epigenetics(+) T cells. Results indicate regulatory T cell (Treg) ontogenesis requires two independent processes, expression of the transcription factor Foxp3 and establishment of Treg epigenetic programs induced by T cell receptor (TCR) stimulation.
2012-11-05 | GSE25252 | GEO
Project description:The central nervous system (CNS) hypothalamus controls systemic metabolism. Inflammatory CNS processes evolving upon exposure to calorie-rich diet are thought to promote impaired metabolic CNS control, thereby triggering obesity and Type-2 diabetes (T2D). However, immune cells relevant for maintaining hypothalamic integrity remain incompletely understood. Here, we identify hypothalamic CD4+Foxp3+regulatory T(Treg) cells which control local tissue-inflammation. Specifically, upon exposure to a calorie-rich diet, a significant decline in hypothalamus-residing Foxp3+Tregs occurred and was accompanied by increased immune activation of CD4+T cells, infiltrating macrophages and microglia. Microglial proteomes of mice exposed to the hypercaloric challenge confirmed characteristics of immune activation; specifically, mRNA expression profiling of hypothalamic CD4+T cells indicated a Th1-mediated inflammatory state evidenced by high levels of Tbx21, Cxcr3, Cd226 and reduced expression of Ccr7 and S1P1 receptors relevant for recruitment to and retention at inflammatory sites. Using Treg depletion and transfer experiments in vivo, we found that Foxp3+Tregs critically limit hypothalamic immune activation induced by hyper-caloric challenge. Our findings open new avenues in the design of tailored concepts to improve immunometabolic health in obesity and T2D.
2025-01-20 | PXD004498 | Pride