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Overproduction of IFNg by Cbl-b deficient CD8+ T cells provides resistance against regulatory T cells and induce potent anti-tumor immunity

ABSTRACT: Overproduction of IFNg by Cbl-b deficient CD8+ T cells provides resistance against regulatory T cells and induce potent anti-tumor immunity

PROVIDER: PRJNA782629 | ENA |

REPOSITORIES: ENA

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			Action	DRS
	SRR17007625_1.fastq.gz	Fastqsanger.gz
	SRR17007625_2.fastq.gz	Fastqsanger.gz
	SRR17007626_1.fastq.gz	Fastqsanger.gz
	SRR17007626_2.fastq.gz	Fastqsanger.gz
	SRR17007627_1.fastq.gz	Fastqsanger.gz

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Similar Datasets

Overproduction of IFNg by Cbl-b deficient CD8+ T cells provides resistance against regulatory T cells and induce potent anti-tumor immunity

Project description:Regulatory T cells are one of the integral components of the adaptive immune system that contribute to the regulation of anti-tumor T cell responses. However, studies have suggested that alterations in T cell signaling networks can result in T cells that are resistant to the suppressive effects of Treg cells. Here, we investigated the role of Cbl-b, an E3 ubiquitin ligase and a negative regulator of TCR signaling pathways, in establishing CD8+ T cell resistance to Treg cell-mediated suppression. First, the absence of Cbl-b rendered CD8+ T cells refractory to the suppressive effects of Treg cells in vitro. Transcriptomic analyses suggested that pathways associated with cellular proliferation and cytokine production likely contribute to the observed phenotype. In particular, hyper-secretion of IFN-g by Cbl-b deficient CD8+ T cells served as a novel mechanism which selectively renders CD8+ T cells less sensitive to suppression by Treg cells. To explore our findings in vivo, we utilized tumor-bearing FoxP3DTR-eGFP mice to confirm that the adoptively transferred tumor-specific CD8+ T cells were susceptible to regulation by Treg cells in the tumor. Unlike the wildtype counterpart, Cbl-b deficient CD8+ T cells were resistant to the suppressive effects of Treg cells in the tumor, and the therapeutic benefit of Cbl-b deficiency was abrogated upon IFN-g blockade. Collectively, our data highlight the role of Cbl-b deficiency and subsequent hyper-secretion of IFN-g as a key mechanism which renders CD8+ T cells resistant to Treg cell-mediated suppression.

2021-12-31 | GSE189350 | GEO

Loss of E3 ubiquitin protein ligase Cbl-b provides protection against UVB-induced cytotoxicity and inflammation.

Project description:The exposure of skin to ultraviolet (UV) radiation results in sunburn cell (SBC) and cyclobutane pyrimidine dimer (CPD) formation and local immune suppression. However, the pathways that regulate these events are poorly understood. Here, we exposed mice to UVB to study the early cytotoxic effects in absence of E3 ubiquitin protein ligase Cbl-b. We observed that Cbl-b-/- mice developed significantly less SBCs and CPDs compared to WT mice. In addition, microarray analysis revealed that loss of Cbl-b-induced cell tolerance genes rather than DNA repair genes. Taken together, our results suggest a novel role of Cbl-b in regulating UV cytotoxicity.

2018-08-15 | GSE79073 | GEO

Quantitative Analysis of Wild Type CBL, CBL 70Z and Y371S 3T3 Stable Cell Transcriptomes

Project description:Cbl (Casitas B-lineage lymphoma) is a prominent post-translational regulator of protein tyrosine kinases (PTKs) that targets activated receptors for ubiquitination-mediated degradation. However, mutations within its E3 ubiquitin ligase activity rendering RING domain are often not sufficient to induce transformation. Rather, a conserved residue (Y371) within the linker helix region (LHR) of Cbl has been a mutational hotspot in myeloproliferative diseases. Interestingly, phosphorylation of Y371 is a prerequisite for Cbl’s ability to ubiquitinate PTKs. We have previously shown that Y371 mutations affect the conformation of Cbl that can be related to its transformation potential. We wanted to investigate for any additional advantage that the Cbl-Y371 mutants could gain over their wild-type counterpart so as to explain their oncogenicity. In our current study, we wanted to investigate the transcriptome profiles of cells overexpressing WT CBL or CBL-70Z, a well-characterized oncogenic CBL mutant lacking residues 366-382 and Y371S a prevalent MDS/MPN CBL mutant. We found an interesting inverse correlationship between the transcriptome of cells expressing WT CBL and the mutant CBLs. The results from this study can be linked to the oncogenic abilities of the mutant CBLs.

2019-10-20 | GSE121176 | GEO

Genome wide transcriptional profiling of c-Cbl deficient hematopoietic stem and progenitor cells

Project description:Expression of genes that are differentially expressed between c-Cbl control and c-Cbl mutant hematopoietic stem and progenitor cells were identified through this approach. Interestingly, several leukemia associated genes, particularly transcription factors, were differentially expressed between c-Cbl WT and c-Cbl mutant hematopoietic stem and progenitor cells. Hematopoietic stem and progenitor cells of c-Cbl control and c-Cbl mutant mice were sorted based on their defined immunophenotype. Gene expression studies were performed using Illumina microarray chips.

2010-08-12 | E-GEOD-23564 | biostudies-arrayexpress

Cbl family proteins are required to maintain the proteome homeostasis in mammary epithelial cells

Project description:EGFR degradation is delayed in Cbl, Cbl-b double-deficient MCF10A but EGF stimulation does not enhance their growth. We performed a transcriptome analysis to gain insights into biological consequences of Cbl, Cbl-b loss in mammary epithelial cells. We compared the transcriptome of MCF10A cells expressing shRNA against Cbl and Cbl-b with control shRNA-expressing cells using Affymetrix U133 Plus 2.0. Each sample was prepared in duplicates. Data were analyzed by GSEA.

2016-03-25 | E-GEOD-67301 | biostudies-arrayexpress

Genome wide transcriptional profiling of c-Cbl deficient hematopoietic stem and progenitor cells

2010-08-12 | GSE23564 | GEO

Overproduction of IL-2 by Cbl-b deficient CD4+ T cells provides resistance against regulatory T cells.

Project description:Regulatory T cells are integral to the regulation of autoimmune and anti-tumor immune responses. However, several studies have suggested that changes in T cell signaling networks can result in T cells that are resistant to the suppressive effects of regulatory T cells. Here, we investigated the role of Cbl-b, an E3 ubiquitin ligase, in establishing resistance to Treg-mediated suppression. We found that the absence of Cbl-b, a negative regulator of multiple TCR signaling pathways, rendered T cells impartial to Treg suppression by regulating cytokine networks leading to improved anti-tumor immunity despite the presence of Treg cells in the tumor. Specifically, Cbl-b KO CD4+FoxP3- T cells hyper-produced IL-2 and together with IL-2 R? upregulation served as an essential mechanism to escape suppression by Treg cells. Furthermore, we report that IL-2 serves as the central molecule required for cytokine-induced Treg resistance. Collectively our data emphasize the role of IL-2 as a key mechanism that renders CD4+ T cells resistant to the inhibitory effects of Treg cells.

| S-EPMC7153846 | biostudies-literature

Cbl family proteins are required to maintain the proteome homeostasis in mammary epithelial cells

2016-03-25 | GSE67301 | GEO

Next generation sequencing transcriptomic analysis of bone marrow derived macrophages within control, Cbl-/-, Cbl-b -/- and DKO genotypes

Project description:The goal of the transcriptomic profiling is to understand what genes or pathway Cbl and Cbl-b regulate for CSF-1R dependent growth signaling

2019-05-01 | GSE130527 | GEO

Comparative analysis of WT CBL and CBL 70Z interactomes.

Project description:Cbl (Casitas B-lineage lymphoma) is a prominent post-translational regulator of protein tyrosine kinases (PTKs) that targets activated receptors for ubiquitination-mediated degradation. However, mutations within its E3 ubiquitin ligase activity rendering RING domain are often not sufficient to induce transformation. Rather, a conserved residue (Y371) within the linker helix region (LHR) of Cbl has been a mutational hotspot in myeloproliferative diseases. Interestingly, phosphorylation of Y371 is a prerequisite for Cblâ€™s ability to ubiquitinate PTKs. We have previously shown that Y371 mutations affect the conformation of Cbl that can be related to its transformation potential. We wanted to investigate for any additional advantage that the Cbl-Y371 mutants could gain over their wild-type counterpart so as to explain their oncogenicity. In our current study, we utilized CBL-70Z, a well-characterized oncogenic CBL mutant lacking residues 366-382 that behave similar to the prevalent MDS/MPN CBL mutants, as an example to explore differences in interactomes between Wild type CBl and CBL 70Z. Any divergent interacting abilities between the two can be used to decipher the mechanism by which the mutants elicit oncogenic transformation.

2021-02-26 | PXD011369 | Pride

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