TNFR2 loss prevents TOX upregulation in CD8+TIM3+ T cells and affords improved responses to tumor and chronic LCMV
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ABSTRACT:
PROVIDER: PRJNA1263524 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR33587900_1.fastq.gz | Fastqsanger.gz | |||
| SRR33587900_2.fastq.gz | Fastqsanger.gz | |||
| SRR33587901_1.fastq.gz | Fastqsanger.gz | |||
| SRR33587901_2.fastq.gz | Fastqsanger.gz | |||
| SRR33587902_1.fastq.gz | Fastqsanger.gz |
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Project description:Preview PDF Abstract Exhaustion represents a collection of programmed T cell differentiation states and an important mode of T cell dysfunction. T cell progression from progenitor to terminal exhaustion is associated with upregulation of the transcription factor TOX and expression of TIM3. Our understanding of factors regulating TOX expression and the transition from progenitor to terminal exhaustion, however, remains incomplete. We reveal here that T cell upregulation of tumor necrosis factor receptor type II (TNFR2) coincides with the gain of phenotypic markers and functions reflective of terminal exhaustion. Meanwhile, knocking out TNFR2 affords a novel population of T cells that express TIM3 but possess diminished TOX levels and functional characteristics of both progenitor and terminally exhausted cells. TIM3+ TNFR2 KO T cells exhibit reduced exhaustion transcriptional programs and enhanced AP1 pathway signatures. Finally, TNFR2 KO mice demonstrate improved T cell-dependent control of tumor and chronic lymphocytic choriomeningitis viral (cLCMV) infection, while pharmacologic antagonism of TNFR2 licenses responses to checkpoint blockade in multiple tumor models.
2025-05-19 | GSE297330 | GEO
Project description:Purpose: Next-generation sequencing (NGS) has revolutionized systems-based analysis of cellular pathways. The goal of this study is to compare the transcriptome of CNS-infiltrating OT-1 WT and Tox-deficient cells during effector phase (7 days after infection with LCMV-OVA)
2018-05-17 | GSE93804 | GEO
Project description:TOX is a nuclear factor essential for the development of CD4+ T cells in the thymus. TOX is found to be aberrantly up-regulated in the skin biopsies and in the blood CD4+ T cells of cutaneous T cell lymphoma. The goal of this study is to identify potential transcriptional targets of TOX in CTCL by comparison between TOX shRNA transfected CTCL cells (Hut78 and HH) and control CTCL cells. Two color experiment. Lentivirus transduced control vector vs. TOX shRNA vectors on Hut78 and HH cell lines. Biological replicates: 3 control replicates, 3 shRNA tansduced replicates for each cell line.
2014-04-29 | E-GEOD-57122 | biostudies-arrayexpress
Project description:TIM3, a T-cell inhibitory receptor, is expressed on exhausted T cells in tumor microenvironment (TME). Anti-TIM3 antibody therapy could alleviate the suppression of tumor-infiltrating lymphocytes (TILs) in IL-2 dependent fashion. We hypothesize that high expression of TIM3 and limited IL-2 in TME facilitate immune evasion. To test that, we engineered anti-TIM3-pro-IL2 to selectively deliver IL-2 to TIM3high TILs by TIM3 antibody and reduce its toxicity with a cis delivery mechanism. Since IL-2 could reduce its activity at acidic pH inside TME, we also screened a low pH-selective IL-2 mutein (IL2V2) with enhanced affinity for IL-2Rβ. We then integrated pro-IL-2 into the anti-TIM3 antibodies in two different forms: TIM3-Rα-MMPs-IL2V2 (TIM3-ProIL2V2) as IL-2 release-form vs TIM3-IL2V2-MMPs-Rα as cis-form after binding to TIM3high T cells, ensuring the need of targeted delivery to TIM3-expressing TILs. Surprisingly, released IL2V2 from TIM3-Rα-MMPs-IL2V2 proved superior in anti-tumor immunity, but not cis delivery form TIM3-IL2V2-MMPs-Rα. Mechanistically, TIM3-ProIL2V2 not only reactivated TIM3+ TILs but also facilitated the activation and expansion of TIM3- T cells which in turn supported a sustained source of TIM3+ effector. TIM3-ProIL2V2 could control multiple tumor models including human tumor in humanized mice, confirming the hypothesis. TIM3-ProIL2V2 activates and expands TIM3-CD8+ T cells to overcome current major unmet medical need: anti-PD-1/L1 resistance. This strategy illustrates the potential of a tailored, low pH-resistant IL2 variant in invigorating both TIM3-negative and positive CD8+ T cells, offering a promising avenue for treating resistant tumors with reduced toxicity.
2025-05-22 | GSE296919 | GEO
Project description:PURPOSE: The goal of this study was to determine the gene expression networks regulated by tumor necrosis factor receptor 2 (TNFR2, or Tnfrsf1b) and to evaluate their potential bearing on immune cell subsets and inflammatory bowel disease (IBD). METHODS: mRNA-seq was performed on isolated distal colons from TNFR2-knockout and wildtype mice. Differentially expressed transcripts were compared to human ulcerative colitis microarray datasets on Gene Expression Omnibus and to mouse immunological expression datasets at the Immunological Genome Project. RESULTS: We identified 252 mouse transcripts whose expressions were significantly altered by the loss of TNFR2. The majority of these transcripts (228 of 252, ~90%) were downregulated in TNFR2-/- colons. TNFR2-regulated genes were able to positively discriminate between ulcerative colitis patients and healthy individuals with ~80% accuracy. Many TNFR2-regulated genes were also highly expressed in CD8+ T cells. CONCLUSIONS: Downregulation of TNFR2 is associated with a gene expression profile that is prominent in IBD and supportive of the role of CD8+ T cells in IBD pathogenesis. MANUSCRIPT ABSTRACT: Increased tumor necrosis factor (TNF) production has been associated with inflammatory bowel disease (IBD), and anti-TNF therapy is a common therapeutic for this patient population. However, the role of TNF or its receptors (TNFR1 and TNFR2) in the immunopathogenesis of inflammatory bowel disease (IBD) remains unclear. Here we report that TNFR2 is protective in spontaneous (IL-10 knockout) and chemically (azoxymethane/dextran sodium sulfate)-induced mouse models of colitis and colitis-associated cancer. Mechanistically, TNFR2-deficiency in hematopoietic cells significantly increased incidence and severity of colitis and colitis-associated cancer characterized by a selective expansion of CD8+ T cells. We identified TNFR2-regulated genes in the colon that were specific for CD8+ T cells, interacted with multiple IBD risk genes, and are important regulators of CD8+ T cell biology. TNFR2 regulated CD8+ T-cell-specific genes that act as genetic susceptibility modifiers for IBD to mitigate the development of a pro-colitogenic milieu. Antibody-mediated depletion of CD8+ T cells prevented colonic inflammation and significantly reduced pathology in IL10-/-/TNFR2-/- deficient mice. Furthermore, adoptive transfer of TNFR2-/- naïve CD8+ T cells resulted in more severe disease than with wildtype naïve CD8+ T cells. Our findings provide insight into the disease modifier role of TNFR2 in the immunopathogenesis of IBD through the modulation of CD8+ T cell responses and support future investigation of this therapeutic target, especially in the subset of IBD patients with CD8+ T-cell dysfunction. Total RNA from distal colons of 8 week-old male wildtype C57Bl/6 and TNFR2-/- mice (n=3 each) was isolated using the PureLink RNA kit (Ambion, Life Technologies). RNA samples were submitted to the Genomic Services Lab at the HudsonAlpha Institute for Biotechnology (Huntsville, AL) for multiplex library preparation, mRNA enrichment, and sequencing. Sequencing was performed to an average depth of 50M paired-end 50bp reads per sample (HiSeq, Illumina, San Diego, CA). Data files containing raw reads were aligned to the mouse genome using Tophat2/Bowtie2. Alignments were assembled into transcript representations with Cufflinks, and statistical tests for differential expression were performed with Cuffdiff 2. An adjusted P value < 0.05 (q<0.05) from the Cuffdiff 2 output was used as the cutoff for statistical significance.
2015-08-11 | E-GEOD-65408 | biostudies-arrayexpress
Project description:Chronic CD8 T-cell stimulation in persisting infections or tumors can induce a stable gene expression program, known as T-cell dysfunction or exhaustion, that limits the cell’s effector functions and anti-viral and anti-tumor immunity. Thus far, the underlaying molecular mechanisms that induce and stabilize this phenotype are vaguely understood. We report here that establishing this program requires the thymocyte selection-associated high mobility group-box protein (Tox). Genetic disruption of Tox augments effector function, decreases the expression of PD-1, and significantly enhances immunopathology. These changes are linked to a failure in fixing the dysfunctional phenotype in the critical Tcf1+ progenitor population and to impaired epigenetic programing. Surprisingly, the gains in effector function co-incide with declining numbers of Tcf1+ cells and result ultimately in reduced total numbers of pathogen-specific T-cells. Thus, we establish Tox as a critical factor for the development of T-cell dysfunction and establish a clear link between CD8 T-cell intrinsic suppression of effector function and protection against immune-pathology.
2019-07-03 | GSE132033 | GEO
Project description:TOX is selectively expressed in tumor-infiltrating CD8 T cells however the role of TOX in peripheral CD8 T cells is not known. The two goals of this study are to elucidate transcriptional changes between TOX-sufficient and TOX-deficient tumor infiltrating CD8 T cells and to elucidate the molecular program induced by TOX overexpression in peripheral CD8 T cells.
2019-06-24 | GSE126973 | GEO
Project description:Subtypes of innate lymphoid cells (ILC), defined by effector function and transcription factor expression, have recently been identified. In the adult, ILC derive from common lymphoid progenitors in bone marrow, although transcriptional regulation of the developmental pathways involved remains poorly defined. TOX is required for development of lymphoid tissue inducer cells, a type of ILC3 required for lymph node organogenesis, and NK cells, a type of ILC1. We show here that production of multiple ILC lineages requires TOX, as a result of TOX-dependent development of common ILC progenitors. Comparative transcriptome analysis demonstrated failure to induce various aspects of the ILC gene program in the absence of TOX, implicating this nuclear factor as a key early determinant of ILC lineage specification. TOX KO vs. wild tyype
2015-04-27 | E-GEOD-65850 | biostudies-arrayexpress
Project description:Chronic CD8 T-cell stimulation in persisting infections or tumors can induce a stable gene expression program, known as T-cell dysfunction or exhaustion, that limits the cell’s effector functions and anti-viral and anti-tumor immunity. Thus far, the underlaying molecular mechanisms that induce and stabilize this phenotype are vaguely understood. We report here that establishing this program requires the thymocyte selection-associated high mobility group-box protein (Tox). Genetic disruption of Tox augments effector function, decreases the expression of PD-1, and significantly enhances immunopathology. These changes are linked to a failure in fixing the dysfunctional phenotype in the critical Tcf1+ progenitor population and to impaired epigenetic programing. Surprisingly, the gains in effector function co-incide with declining numbers of Tcf1+ cells and result ultimately in reduced total numbers of pathogen-specific T-cells. Thus, we establish Tox as a critical factor for the development of T-cell dysfunction and establish a clear link between CD8 T-cell intrinsic suppression of effector function and protection against immune-pathology. The terms acute and chronic samples refer to P14 T-cells that were initially activated in acute LCMV (Armstrong) or chronic LCMV (clone-13) infections. 4 weeks later, the P14 T cells were collected, transferred into naive mice, and both then re-expanded in acute LCMV (Armstrong) infection. 8 days later P14 T-cells were collected and analysed.
2019-07-03 | GSE132027 | GEO
Project description:PURPOSE: The goal of this study was to determine the gene expression networks regulated by tumor necrosis factor receptor 2 (TNFR2, or Tnfrsf1b) and to evaluate their potential bearing on immune cell subsets and inflammatory bowel disease (IBD). METHODS: mRNA-seq was performed on isolated distal colons from TNFR2-knockout and wildtype mice. Differentially expressed transcripts were compared to human ulcerative colitis microarray datasets on Gene Expression Omnibus and to mouse immunological expression datasets at the Immunological Genome Project. RESULTS: We identified 252 mouse transcripts whose expressions were significantly altered by the loss of TNFR2. The majority of these transcripts (228 of 252, ~90%) were downregulated in TNFR2-/- colons. TNFR2-regulated genes were able to positively discriminate between ulcerative colitis patients and healthy individuals with ~80% accuracy. Many TNFR2-regulated genes were also highly expressed in CD8+ T cells. CONCLUSIONS: Downregulation of TNFR2 is associated with a gene expression profile that is prominent in IBD and supportive of the role of CD8+ T cells in IBD pathogenesis. MANUSCRIPT ABSTRACT: Increased tumor necrosis factor (TNF) production has been associated with inflammatory bowel disease (IBD), and anti-TNF therapy is a common therapeutic for this patient population. However, the role of TNF or its receptors (TNFR1 and TNFR2) in the immunopathogenesis of inflammatory bowel disease (IBD) remains unclear. Here we report that TNFR2 is protective in spontaneous (IL-10 knockout) and chemically (azoxymethane/dextran sodium sulfate)-induced mouse models of colitis and colitis-associated cancer. Mechanistically, TNFR2-deficiency in hematopoietic cells significantly increased incidence and severity of colitis and colitis-associated cancer characterized by a selective expansion of CD8+ T cells. We identified TNFR2-regulated genes in the colon that were specific for CD8+ T cells, interacted with multiple IBD risk genes, and are important regulators of CD8+ T cell biology. TNFR2 regulated CD8+ T-cell-specific genes that act as genetic susceptibility modifiers for IBD to mitigate the development of a pro-colitogenic milieu. Antibody-mediated depletion of CD8+ T cells prevented colonic inflammation and significantly reduced pathology in IL10-/-/TNFR2-/- deficient mice. Furthermore, adoptive transfer of TNFR2-/- naïve CD8+ T cells resulted in more severe disease than with wildtype naïve CD8+ T cells. Our findings provide insight into the disease modifier role of TNFR2 in the immunopathogenesis of IBD through the modulation of CD8+ T cell responses and support future investigation of this therapeutic target, especially in the subset of IBD patients with CD8+ T-cell dysfunction.
2015-08-11 | GSE65408 | GEO