Browse
Submit Data
Databases
API
Help

Unknown,Transcriptomics,Genomics,Proteomics

Dataset Information

0 Views

0 Connections

0 Citations

0 Reanalyses

0 Downloads

Omics score: 0

Direct regulation of T cell exhaustion by NFAT [RNA-Seq]

ABSTRACT: During persistent antigen stimulation, CD8+ cytolytic T cells (CTL) show a gradual decrease in effector function, or “exhaustion”, which impairs the immune response to tumors and infections. Here we show that NFAT, a transcription factor with an established role in T cell activation, in parallel controls a second transcriptional program conferring the characteristic features of CD8+ T cell exhaustion, including upregulation of genes encoding inhibitory cell surface receptors and diminished TCR signaling. Expression of an engineered NFAT1, which induces this negative regulatory program in the absence of the effector program, interferes with the ability of CD8+ T cells to protect against Listeria infection or attenuate tumor growth in vivo. NFAT elicits this second program of gene expression in large part by binding to a subset of the sites occupied by NFAT during a typical effector response, suggesting that a balance between the two pathways determines the outcome of TCR signaling. Understanding the role of CA-RIT-NFAT1 in T cells

ORGANISM(S): Mus musculus

SUBMITTER: Tarmo Äijö

PROVIDER: E-GEOD-64408 | biostudies-arrayexpress |

REPOSITORIES: biostudies-arrayexpress

ACCESS DATA

Json Xml

Similar Datasets

Direct regulation of T cell exhaustion by NFAT [ChIP-Seq]

Project description:During persistent antigen stimulation, CD8+ cytolytic T cells (CTL) show a gradual decrease in effector function, or “exhaustion”, which impairs the immune response to tumors and infections. Here we show that NFAT, a transcription factor with an established role in T cell activation, in parallel controls a second transcriptional program conferring the characteristic features of CD8+ T cell exhaustion, including upregulation of genes encoding inhibitory cell surface receptors and diminished TCR signaling. Expression of an engineered NFAT1, which induces this negative regulatory program in the absence of the effector program, interferes with the ability of CD8+ T cells to protect against Listeria infection or attenuate tumor growth in vivo. NFAT elicits this second program of gene expression in large part by binding to a subset of the sites occupied by NFAT during a typical effector response, suggesting that a balance between the two pathways determines the outcome of TCR signaling. Determination of NFAT1 binding sites in CD8 T cells in vitro

2015-02-13 | E-GEOD-64407 | biostudies-arrayexpress

Direct regulation of T cell exhaustion by NFAT [RNA-Seq]

2015-02-13 | GSE64408 | GEO

Direct regulation of T cell exhaustion by NFAT [ChIP-Seq]

2015-02-13 | GSE64407 | GEO

Transcriptome differences in HCC infiltrated CD8+ T cells in effector and exhaustion state

Project description:CD8+ T cells isolated from HCC tissue were divided into three groups: PD1-TIM3- CD8+ TILs, exhibiting full effector function; PD1-intTIM3+ CD8+ TILs, exhibiting partial exhaustion; and PD1-hiTIM3+ CD8+ TILs, exhibiting severe exhaustion, as reflected by the differences in their ability to produce effector cytokines respectively. Transcriptome sequence analysis was performed to investigate the gene expression profile was performed.

2019-12-31 | E-MTAB-7278 | biostudies-arrayexpress

Metabolic exhaustion of T cells in chronic infection is mediated by inhibitory receptor PD-1 and T cell receptor dependent transcription factor IRF4

Project description:During chronic stimulation T cells acquire an exhausted phenotype characterized by expression of multiple inhibitory receptors and down-modulation of effector function. While this is required for the protection of the organism from excessive immunopathology, it also prevents successful immunity against persistent viruses or tumor cells. Here we demonstrate that CD8+ T cell exhaustion is characterized by a progressive decline in cellular metabolism. Exhausted T cells exhibit reduced metabolic reserve, impaired fatty acid oxidation and production of mitochondrial reactive oxygen species (ROS). Blockade of inhibitory PD-1/PD-L1 signaling rescued mitochondrial biogenesis, oxidative phosphorylation and ROS production, which was required for efficient restoration of cellular expansion and effector function. Expression of inhibitory receptors and impaired metabolic function was fuled by high amounts of IRF4, BATF and NFAT, which formed a TCR-responsive transcriptional circuit that sustained the transcriptional network responsible for T cell exhaustion.

2018-01-01 | GSE84820 | GEO

Genome wide mapping of NFAT1 binding sites in dendritic cells and of chromatin state in steady and dectin-1 activated dendritic cell line D1

Project description:We generated genome-wide chromatin-state maps of mouse dendritic cells in steady and dectin-1 activated with or without NFAT inhibitor FK506. We found the differential H3K4me3 signatures in these cells. This study provides the epigenetic signatures of steady, dectin-1activated with or without NFAT inhibition. We also generated stable dendritic cell line D1 expressing a V5 tagging NFAT1. This cell line was used to map the global binding sites of NFAT1 upon dectin-1 activation with 10ug/ml curdlan for 30 minutes. examine NFAT1-v5 genome wide binding sites and differential H3K4me3 epigenetic modification in steady, dectinn-1 activated with or without NFAT inhibiton.

2015-01-05 | E-GEOD-59998 | biostudies-arrayexpress

NFAT signaling is indispensable for persistent memory responses of MCMV-specific CD8+ T cells

Project description:Cytomegalovirus (CMV) induces a uniquely robust and persistent T cell response, where the size of the antigen-specific population does not contract, but rather inflates during viral latency. It has been proposed that intermittent engagements of T cell receptors (TCRs) by viral antigens upon subclinical episodes of virus reactivation feed the inflation of CMV-specific memory cells, but evidence of TCR engagement has remained lacking. Nuclear factor of activated T cells (NFAT) is a family of transcription factors, where NFATc1, NFATc2 and NFATc3 are expressed in mature T lymphocytes, of which NFATc1 and NFATc2 are the dominating family members. In an in vivo model of mouse CMV (MCMV) infection of mice with genetic ablation of NFAT signaling, we show a selective impact of this defect in TCR signaling on the long-term inflation of MCMV-specific CD8 T cell responses, while the initial responses to acute infection remain largely maintained. NFATc1 ablation had an immediate effect, while ablation of both NFATs had the most profound influence. In presence of other lymphocytes, NFAT deficiency in T cells had no effect on virus replication or latency, but in adoptive immunotherapy of RAG2-deficient recipient mice, the lack of both NFAT molecules in solely transplanted CD8+ T cells uncovered their decreased antiviral efficacy. We characterized CD8 responses in absence of either or both NFAT molecules by transcriptome analyses and demonstrate that T cell-intrinsic NFAT is not necessary for CD8 T cell priming, but rather for their maturation towards effector memory and in particular the effector cells, which dominate the pool of inflationary cells.

2024-01-25 | GSE228527 | GEO

Dissecting the dynamic changes of 5-hydroxymethylcytosine in T cell development and differentiation [RNA-Seq]

Project description:The discovery of TET proteins, enzymes that oxidize 5-methylcytosine (5mC) in DNA, has revealed novel mechanisms for the regulation of DNA methylation. We have mapped 5-hydroxymethylcytosine (5hmC) at different stages of T cell development in the thymus and T cell differentiation in the periphery. We show that 5hmC is enriched in the gene body of highly expressed genes at all developmental stages, and that its presence correlates positively with gene expression. Further emphasizing the connection with gene expression, we find that 5hmC is enriched in active thymus-specific enhancers, and that genes encoding key transcriptional regulators display high intragenic 5hmC levels in precursor cells at those developmental stages where they exert a positive effect. Our data constitute a valuable resource that will facilitate detailed analysis of the role of 5hmC in T cell development and differentiation. Transcriptome profiling of naïve CD4 and CD8 cells

2014-08-04 | E-GEOD-59121 | biostudies-arrayexpress

BATF and IRF4 cooperate to counter exhaustion in tumour-infiltrating CAR T cells (RNA-seq)

Project description:Cooperative interactions among transcription factors are essential for gene transcription. We previously showed that NFAT and AP-1 (Fos-Jun) transcription factors cooperate to promote the effector functions of T cells, but that under conditions where it is unable to cooperate with AP-1, NFAT imposes a negative feedback programme of T cell hyporesponsiveness (“exhaustion”). Here we show that BATF and IRF4 cooperate to counter T cell exhaustion. Overexpression of Batf in CD8+ 42 T cells expressing a chimeric antigen receptor (CAR) promoted the survival and expansion of tumour-infiltrating CAR T cells, increased their production of effector cytokines, decreased their expression of inhibitory receptors and the exhaustion-associated transcription factor TOX, and led to the generation of long-lived memory T cells that controlled tumour recurrence. These responses were dependent on the BATF-IRF interaction, since cells expressing a Batf mutant unable to interact with Irf4 did not survive in tumours and did not effectively delay tumour growth. We suggest that BATF overexpression is a therapeutically viable option for improving the anti-tumour responses of CAR TILs, by skewing their phenotypes and transcriptional profiles away from exhaustion and towards increased effector function.

2021-07-13 | GSE154745 | GEO

BATF and IRF4 cooperate to counter exhaustion in tumour-infiltrating CAR T cells (ChIP-seq)

2021-07-13 | GSE154743 | GEO