Browse
Submit Data
Databases
API
Help

Dataset Information

0 Views

0 Connections

0 Citations

0 Reanalyses

0 Downloads

Omics score: 0

T cell receptor-dependent regulation of lipid rafts controls naive CD8+ T cell homeostasis.

ABSTRACT: T cell receptor (TCR) contact with self ligands keeps T cells alive and is shown here to cause naive CD8(+), but not CD4(+), T cells to be hypersensitive to certain gamma(c) cytokines, notably interleukin (IL)-2, IL-15, and IL-7. Hypersensitivity of CD8(+) T cells to IL-2 was dependent on a low-level TCR signal, associated with high expression of CD5 and GM1, a marker for lipid rafts, and was abolished by disruption of lipid rafts. By contrast, CD4(+) T cells expressed low amounts of GM1 and were unresponsive to IL-2. Physiologically, sensitivity to IL-7 and IL-15 maintains survival of resting CD8(+) T cells, whereas sensitivity to IL-2 may be irrelevant for normal homeostasis but crucial for the immune response. Thus, TCR contact with antigen upregulates GM1 and amplifies responsiveness of naive CD8(+) T cells to IL-2, thereby making the cells highly sensitive to exogenous IL-2 from CD4(+) T helper cells.

SUBMITTER: Cho JH

PROVIDER: S-EPMC2830358 | biostudies-literature | 2010 Feb

REPOSITORIES: biostudies-literature

ACCESS DATA

Json Xml

Publications

T cell receptor-dependent regulation of lipid rafts controls naive CD8+ T cell homeostasis.

Cho Jae-Ho JH Kim Hee-Ok HO Surh Charles D CD Sprent Jonathan J

Immunity 20100204 2

T cell receptor (TCR) contact with self ligands keeps T cells alive and is shown here to cause naive CD8(+), but not CD4(+), T cells to be hypersensitive to certain gamma(c) cytokines, notably interleukin (IL)-2, IL-15, and IL-7. Hypersensitivity of CD8(+) T cells to IL-2 was dependent on a low-level TCR signal, associated with high expression of CD5 and GM1, a marker for lipid rafts, and was abolished by disruption of lipid rafts. By contrast, CD4(+) T cells expressed low amounts of GM1 and wer ...[more]

PMID: 20137986

Similar Datasets

HDAC1 controls CD8+ T cell homeostasis and antiviral response.

Project description:Reversible lysine acetylation plays an important role in the regulation of T cell responses. HDAC1 has been shown to control peripheral T helper cells, however the role of HDAC1 in CD8+ T cell function remains elusive. By using conditional gene targeting approaches, we show that LckCre-mediated deletion of HDAC1 led to reduced numbers of thymocytes as well as peripheral T cells, and to an increased fraction of CD8+CD4- cells within the CD3/TCR?lo population, indicating that HDAC1 is essential for the efficient progression of immature CD8+CD4- cells to the DP stage. Moreover, CD44hi effector CD8+ T cells were enhanced in mice with a T cell-specific deletion of HDAC1 under homeostatic conditions and HDAC1-deficient CD44hi CD8+ T cells produced more IFN? upon ex vivo PMA/ionomycin stimulation in comparison to wild-type cells. Naïve (CD44l°CD62L+) HDAC1-null CD8+ T cells displayed a normal proliferative response, produced similar amounts of IL-2 and TNF?, slightly enhanced amounts of IFN?, and their in vivo cytotoxicity was normal in the absence of HDAC1. However, T cell-specific loss of HDAC1 led to a reduced anti-viral CD8+ T cell response upon LCMV infection and impaired expansion of virus-specific CD8+ T cells. Taken together, our data indicate that HDAC1 is required for the efficient generation of thymocytes and peripheral T cells, for proper CD8+ T cell homeostasis and for an efficient in vivo expansion and activation of CD8+ T cells in response to LCMV infection.

| S-EPMC4204873 | biostudies-literature

Lipid rafts and regulation of the cytoskeleton during T cell activation.

Project description:The ability of polarized cells to initiate and sustain directional responses to extracellular signals is critically dependent on direct communication between spatially organized signalling modules in the membrane and the underlying cytoskeleton. Pioneering work in T cells has shown that the assembly of signalling modules critically depends on the functional compartmentalization of membrane lipids into ordered microdomains or lipid rafts. The significance of rafts in T cell activation lies not only in their ability to recruit the signalling partners that eventually assemble into a mature immunological synapse but also in their ability to regulate actin dynamics and recruit cytoskeletal associated proteins, thereby achieving the structural polarization underlying stability of the synapse-a critical prerequisite for activation to be sustained. Lipid rafts vary quite considerably in size and visualizing the smallest of them in vivo has been challenging. Nonetheless it is now been shown quite convincingly that a surprisingly large proportion-in the order of 50%-of external membrane lipids (chiefly cholesterol and glycosphingolipids) can be dynamically localized in these liquid ordered rafts. Complementary inner leaflet rafts are less well characterized, but contain phosphoinositides as an important functional component that is crucial for regulating the behaviour of the actin cytoskeleton. This paper provides an overview of the interdependency between signalling and cytoskeletal polarization, and in particular considers how regulation of the cytoskeleton plays a crucial role in the consolidation of rafts and their stabilization into the immunological synapse.

| S-EPMC1569545 | biostudies-literature

Vitamin D receptor expression controls proliferation of naive CD8+ T cells and development of CD8 mediated gastrointestinal inflammation.

Project description:BackgroundVitamin D receptor (VDR) deficiency contributes to the development of experimental inflammatory bowel disease (IBD) in several different models. T cells have been shown to express the VDR, and T cells are targets of vitamin D. In this article we determined the effects of VDR expression on CD8+ T cells.ResultsVDR KO CD8+ T cells, but not WT CD8+ T cells, induced colitis in Rag KO recipients. In addition, co-transfer of VDR KO CD8+ T cells with naïve CD4+ T cells accelerated colitis development. The more severe colitis was associated with rapidly proliferating naïve VDR KO CD8+ T cells and increased IFN-? and IL-17 in the gut. VDR KO CD8+ T cells proliferated in vitro without antigen stimulation and did not downregulate CD62L and upregulate CD44 markers following proliferation that normally occurred in WT CD8+ T cells. The increased proliferation of VDR KO CD8+ cells was due in part to the higher production and response of the VDR KO cells to IL-2.ConclusionsOur data indicate that expression of the VDR is required to prevent replication of quiescent CD8+ T cells. The inability to signal through the VDR resulted in the generation of pathogenic CD8+ T cells from rapidly proliferating cells that contributed to the development of IBD.

| S-EPMC3923390 | biostudies-literature

RORα controls hepatic lipid homeostasis via negative regulation of PPARγ transcriptional network.

Project description:The retinoic acid receptor-related orphan receptor-α (RORα) is an important regulator of various biological processes, including cerebellum development, circadian rhythm and cancer. Here, we show that hepatic RORα controls lipid homeostasis by negatively regulating transcriptional activity of peroxisome proliferators-activated receptor-γ (PPARγ) that mediates hepatic lipid metabolism. Liver-specific Rorα-deficient mice develop hepatic steatosis, obesity and insulin resistance when challenged with a high-fat diet (HFD). Global transcriptome analysis reveals that liver-specific deletion of Rorα leads to the dysregulation of PPARγ signaling and increases hepatic glucose and lipid metabolism. RORα specifically binds and recruits histone deacetylase 3 (HDAC3) to PPARγ target promoters for the transcriptional repression of PPARγ. PPARγ antagonism restores metabolic homeostasis in HFD-fed liver-specific Rorα deficient mice. Our data indicate that RORα has a pivotal role in the regulation of hepatic lipid homeostasis. Therapeutic strategies designed to modulate RORα activity may be beneficial for the treatment of metabolic disorders.Hepatic steatosis development may result from dysregulation of lipid metabolism, which is finely tuned by several transcription factors including the PPAR family. Here Kim et al. show that the nuclear receptor RORα inhibits PPARγ-mediated transcriptional activity by interacting with HDAC3 and competing for the promoters of lipogenic genes.

| S-EPMC5534431 | biostudies-literature

TRPM8-androgen receptor association within lipid rafts promotes prostate cancer cell migration.

Project description:In prostate carcinogenesis, androgens are known to control the expression of the transient receptor potential melastatin 8 (TRPM8) protein via activation of androgen receptor (AR). Overexpression and/or activity of TRPM8 channel was shown to suppress prostate cancer (PCa) cell migration. Here we report that at certain concentrations androgens facilitate PCa cell migration. We show that underlying mechanism is inhibition of TRPM8 by activated AR which interacts with the channel within lipid rafts microdomains of the plasma membrane. Thus, our study has identified an additional nongenomic mechanism of the TRPM8 channel regulation by androgens that should be taken into account upon the development of novel therapeutic strategies.

| S-EPMC6733924 | biostudies-literature

Macrophage ABCA1 reduces MyD88-dependent Toll-like receptor trafficking to lipid rafts by reduction of lipid raft cholesterol.

Project description:We previously showed that macrophages from macrophage-specific ATP-binding cassette transporter A1 (ABCA1) knockout (Abca1(-M/-M)) mice had an enhanced proinflammatory response to the Toll-like receptor (TLR) 4 agonist, lipopolysaccharide (LPS), compared with wild-type (WT) mice. In the present study, we demonstrate a direct association between free cholesterol (FC), lipid raft content, and hyper-responsiveness of macrophages to LPS in WT mice. Abca1(-M/-M) macrophages were also hyper-responsive to specific agonists to TLR2, TLR7, and TLR9, but not TLR3, compared with WT macrophages. We hypothesized that ABCA1 regulates macrophage responsiveness to TLR agonists by modulation of lipid raft cholesterol and TLR mobilization to lipid rafts. We demonstrated that Abca1(-M/-M) vs. WT macrophages contained 23% more FC in isolated lipid rafts. Further, mass spectrometric analysis suggested raft phospholipid composition was unchanged. Although cell surface expression of TLR4 was similar between Abca1(-M/-M) and WT macrophages, significantly more TLR4 was distributed in membrane lipid rafts in Abca1(-M/-M) macrophages. Abca1(-M/-M) macrophages also exhibited increased trafficking of the predominantly intracellular TLR9 into lipid rafts in response to TLR9-specific agonist (CpG). Collectively, our data suggest that macrophage ABCA1 dampens inflammation by reducing MyD88-dependent TLRs trafficking to lipid rafts by selective reduction of FC content in lipid rafts.

| S-EPMC2952560 | biostudies-literature

NRF2-dependent regulation of the prostacyclin receptor PTGIR drives CD8 T cell exhaustion.

Project description:The progressive decline of CD8 T cell effector function-also known as terminal exhaustion-is a major contributor to immune evasion in cancer. Yet, the molecular mechanisms that drive CD8 T cell dysfunction remain poorly understood. Here, we report that the Kelch-like ECH-associated protein 1 (KEAP1)-Nuclear factor erythroid 2-related factor 2 (NRF2) signaling axis, which mediates cellular adaptations to oxidative stress, directly regulates CD8 T cell exhaustion. Transcriptional profiling of dysfunctional CD8 T cells from chronic infection and cancer reveals enrichment of NRF2 activity in terminally exhausted (Texterm) CD8 T cells. Increasing NRF2 activity in CD8 T cells (via conditional deletion of KEAP1) promotes increased glutathione production and antioxidant defense yet accelerates the development of terminally exhausted (PD-1+TIM-3+) CD8 T cells in response to chronic infection or tumor challenge. Mechanistically, we identify PTGIR, a receptor for the circulating eicosanoid prostacyclin, as an NRF2-regulated protein that promotes CD8 T cell dysfunction. Silencing PTGIR expression restores the anti-tumor function of KEAP1-deficient T cells. Moreover, lowering PTGIR expression in CD8 T cells both reduces terminal exhaustion and enhances T cell effector responses (i.e. IFN-γ and granzyme production) to chronic infection and cancer. Together, these results establish the KEAP1-NRF2 axis as a metabolic sensor linking oxidative stress to CD8 T cell dysfunction and identify the prostacyclin receptor PTGIR as an NRF2-regulated immune checkpoint that regulates CD8 T cell fate decisions between effector and exhausted states.

| S-EPMC11230227 | biostudies-literature

Aryl hydrocarbon receptor controls murine mast cell homeostasis.

Project description:We propose that the aryl hydrocarbon receptor (AhR), a unique chemical sensor, is critical in controlling mast cell differentiation, growth, and function in vitro and in vivo. In antigen-stimulated mast cells, exposure to AhR ligands resulted in a calcium- and reactive oxygen species (ROS)-dependent increase of reversible oxidation in and reduced activity of SHP-2 phosphatase, leading to enhanced mast cell signaling, degranulation, and mediator and cytokine release, as well as the in vivo anaphylactic response. Surprisingly, significant mast cell deficiency was noted in AhR-null mice due to defective calcium signaling and mitochondrial function, concomitant with reduced expression of c-kit and cytosolic STAT proteins, as well as enhanced intracellular ROS and apoptosis. Consequently, AhR-null mast cells responded poorly to stimulation, demonstrating a critical role of AhR signaling in maintaining mast cell homeostasis.

| S-EPMC3630832 | biostudies-literature

Compartmentalization of the exocyst complex in lipid rafts controls Glut4 vesicle tethering.

Project description:Lipid raft microdomains act as organizing centers for signal transduction. We report here that the exocyst complex, consisting of Exo70, Sec6, and Sec8, regulates the compartmentalization of Glut4-containing vesicles at lipid raft domains in adipocytes. Exo70 is recruited by the G protein TC10 after activation by insulin and brings with it Sec6 and Sec8. Knockdowns of these proteins block insulin-stimulated glucose uptake. Moreover, their targeting to lipid rafts is required for glucose uptake and Glut4 docking at the plasma membrane. The assembly of this complex also requires the PDZ domain protein SAP97, a member of the MAGUKs family, which binds to Sec8 upon its translocation to the lipid raft. Exocyst assembly at lipid rafts sets up targeting sites for Glut4 vesicles, which transiently associate with these microdomains upon stimulation of cells with insulin. These results suggest that the TC10/exocyst complex/SAP97 axis plays an important role in the tethering of Glut4 vesicles to the plasma membrane in adipocytes.

| S-EPMC1446102 | biostudies-literature

p53-dependent programmed necrosis controls germ cell homeostasis during spermatogenesis.

Project description:The importance of regulated necrosis in pathologies such as cerebral stroke and myocardial infarction is now fully recognized. However, the physiological relevance of regulated necrosis remains unclear. Here, we report a conserved role for p53 in regulating necrosis in Drosophila and mammalian spermatogenesis. We found that Drosophila p53 is required for the programmed necrosis that occurs spontaneously in mitotic germ cells during spermatogenesis. This form of necrosis involved an atypical function of the initiator caspase Dronc/Caspase 9, independent of its catalytic activity. Prevention of p53-dependent necrosis resulted in testicular hyperplasia, which was reversed by restoring necrosis in spermatogonia. In mouse testes, p53 was required for heat-induced germ cell necrosis, indicating that regulation of necrosis is a primordial function of p53 conserved from invertebrates to vertebrates. Drosophila and mouse spermatogenesis will thus be useful models to identify inducers of necrosis to treat cancers that are refractory to apoptosis.

| S-EPMC5629030 | biostudies-literature

OmicsDI is part of the ELIXIR infrastructure

OmicsDI is an Elixir interoperability service. Learn more ›

Tweets

OmicsDI Databases

PRIDE
PeptideAtlas
MassIVE
JPOST Repository
Physiome Model Repository

EGA
EVA
ENA
LINCS
PAXDB
Cell Collective

MetaboLights
Metabolomics Workbench
MetabolomeExpress
GNPS
BioModels
FAIRDOMHub

ArrayExpress
dbGaP
ExpressionAtlas
GEO
NODE

Information

Databases
Help
API
Contact us
Code on GitHub
Terms of use
Submit Data