Th17-Derived Th1 Cells Resemble Progenitor Exhausted CD4+ T Cells and Exhibit Augmented Anti-tumor Efficacy
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PROVIDER: PRJNA1024437 | ENA |
REPOSITORIES: ENA
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Project description:Th17 cells exhibit superior stemness and differentiation capabilities. Under specific conditions, they can be induced to differentiate into various subtypes. Here we reported that Th17-derived Th1 cells, when compared to conventional Th1 and Th17 cells, manifest less exhausted phenotype and enhanced anti-tumor activity.
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Project description:Tumor-specific T cells are frequently exhausted by chronic antigenic stimulation. To explore new pathways for reinvigoration of anti-tumor immune functions, we developed a human ex vivo exhaustion model by repetitive antigenic stimulation of primary CD8 T cells. This results in T cells that resemble patient-derived T cells in tumors on a phenotypic and transcriptional level.
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Project description:CD4 T cells were activated using CD3/CD28 antibodies in the presence of IL2 and IL12, to generate Th1 cells. Th1 cells were maintained and expanded in IL2 and IL12, on D5 Th1 cells were sorted for CD4+ expression and DAP1 exclusion. After flow sorting, live TH1 cells were resuspended (1e6 per ml) in methionine free RPMI, supplemented with 10% dialysed FBS, IL2 and IL12, and with L-methionine (100μM, or 1μM). Cells were cultured for 5 hrs before collection for proteomics processing.
2019-03-29 | PXD012053 | Pride
Project description:This study provides evidence on the molecular mechanisms by which P2RX7 signaling promotes Th1 cell differentiation. P2RX7 induces T-bet expression and aerobic glycolysis in splenic CD4+ T cells that respond to malaria, at a time prior to Th1/Tfh polarization. Cell-intrinsic P2RX7 signaling sustains the glycolytic pathway and causes bioenergetic mitochondrial stress in activated CD4+ T cells. We also show in vitro the phenotypic similarities of Th1-polarized CD4+ T cells that do not express P2RX7 and those in which the glycolytic pathway is pharmacologically inhibited. In addition, ATP synthase blockade in vitro and the consequent inhibition of oxidative phosphorylation, which forces cells to use aerobic glycolysis, is sufficient to promote rapid CD4+ T cell proliferation and polarization to the Th1 profile in the absence of P2RX7. These data demonstrate that P2RX7-mediated metabolic reprograming for aerobic glycolysis is a key event for Th1 cell differentiation and suggest that ATP synthase inhibition is a fundamental mechanism by which P2X7 signaling induces the Th1 response.
2023-03-08 | PXD037754 | Pride
Project description:CD8 T cells normally differentiate from resting naïve T cells into function effector and then memory CD8 T cells following acute infections. During chronic viral infections, however, virus-specific CD8 T cells often become exhausted. We used microarrays to examine the gene expression differences between naive, effector, memory and exhausted virus-specific CD8 T cells following lymphocytic choriomeningitis virus infection. Experiment Overall Design: Three or four independent samples were sorted by flow cytometry for each cell type (naive, effector, memory and exhausted) virus-specific CD8 T cells. RNA was extracted and hybridized to Affymetrix microarrays.
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Project description:Tumor-specific T cells are frequently exhausted by chronic antigenic stimulation. To explore new pathways for reinvigoration of anti-tumor immune functions, we developed a human ex vivo exhaustion model by repetitive antigenic stimulation of primary CD8 T cells. This results in T cells that resemble patient-derived T cells in tumors on a phenotypic and transcriptional level.
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Project description:T helper (Th) cells play critical functions in response to infectious, allergic, and autoimmune diseases. Upon exposure to a given infectious agent or stimulus, different individuals vary in their Th cell responses, influencing the final disease outcome. To investigate the genetic factors that contribute to such differential immune responses, we performed a haplotype-based computational genetic analysis based on the phenotypic profiles of in vitro differentiated Th1 cells from 16 inbred mouse strains. And we identified genes including that encoding the p53 family protein, p73, with SNP patterns that correlated with the quantitative difference in IFNγ expression. Overexpression of p73 inhibited Th1 differentiation, as evaluated by reduced IFNγ expression, whereas shRNA knockdown or knockout of the p73 gene augmented IFNγ production. An inhibitory effect of p73 on Th1 differentiation was also observed in Stat1-/- cells, indicating that the effect was at least partially independent of STAT1. The DNA-binding activity of p73 is required for its inhibitory effect on IFNγ expression, as deletion of p73 DNA binding domain abolished IFNγ inhibition. A global gene expression analysis showed that 206 genes are differentially expressed more than two-fold in response to p73 overexpression, and 55 of these are direct target genes of p73 in Th1 cells, based on ChIP-seq analysis. p73 binding peaks were identified at a range of genes, including at the Il12rb2, Il24, and Il2ra loci, and p73 was implicated for regulating these genes based on reporter constructs containing WT or mutant p73 binding sites. Furthermore, p73 deficient mice had reduced disease severity in MOG induced EAE, with increased IFNg production from spinal cord infiltrating cells. Thus, p73 is a novel regulator of IFNγ expression, revealing a previously unanticipated role for p73 in Th1 cell differentiation.
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Project description:Exhausted T cells express multiple co-inhibitory molecules that impair their function and limit immunity to chronic viral infection. Defining novel markers of exhaustion is important both for identifying and potentially reversing T cell exhaustion. Herein, we show that the ectonucleotidse CD39 is a marker of exhausted CD8+ T cells. CD8+ T cells specific for HCV or HIV express high levels of CD39, but those specific for EBV and CMV do not. CD39 expressed by CD8+ T cells in chronic infection is enzymatically active, co-expressed with PD-1, marks cells with a transcriptional signature of T cell exhaustion and correlates with viral load in HIV and HCV. In the mouse model of chronic Lymphocytic Choriomeningitis Virus infection, virus-specific CD8+ T cells contain a population of CD39high CD8+ T cells that is absent in functional memory cells elicited by acute infection. This CD39high CD8+ T cell population is enriched for cells with the phenotypic and functional profile of terminal exhaustion. These findings provide a new marker of T cell exhaustion, and implicate the purinergic pathway in the regulation of T cell exhaustion. CD8+ T cells from subjects with HCV infection were sorted and pelleted and re-suspended in TRIzol (Invitrogen). RNA extraction was performed using the RNAdvance Tissue Isolation kit (Agencourt). Concentrations of total RNA were determined with a Nanodrop spectrophotometer or Ribogreen RNA quantification kits (Molecular Probes/Invitrogen). RNA purity was determined by Bioanalyzer 2100 traces (Agilent Technologies). Total RNA was amplified with the WT-Ovation Pico RNA Amplification system (NuGEN) according to the manufacturer's instructions. After fragmentation and biotinylation, cDNA was hybridized to HG-U133A 2.0 microarrays (Affymetrix).
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Project description:To understand the molecular mechanism underlying the IL-6-mediated attenuation of Th1 differentiation in tumor-bearing animals, we have employed whole genome microarray expression profiling of CD4+ T cells isolated from tumor-bearing mice. In order to distingish the effect of IL-6/sIL-6R signaling augmented in tumor-bearing mice from the effecct of other tumor-derived signals, we isolated CD4+ T cells that were primed in tumor free-mice and in the mice inoculated with ovalbumin (OVA)-expressing MCA205 fibrosamcoma, in conjunction of anti-IL-6R Ab injection. We found that Th2-like gene signature such as Il4, IL10, Ccr4, and c-maf was up-regulated in CD4+ T cells primed in tumor-bearing mice. However,the expression of other Th2 master regulator Gata3 gene, or Tfh-related genes (Bcl6, Cxcr5, and Batf) was not substantially augmented in tumor-bearing mice as compared with those in tumor-free mice. These expressions were abrogated by IL-6R blockade, suggesting that the expression of these Th2-like gene set and the other IL-6 signal-dependent genes like Klf1, Bcl11a, and Klf4 are candidate regulators responsible for IL-6 signaling-mediated Th1 inhibition in tumor-bearing animals.
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