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Acute transcriptional effects of IL-6 on murine naive CD8 T cells

ABSTRACT: Interleukin 6 (IL-6) is a pleiotropic cytokine with diverse roles in homeostasis, inflammation, and cancer. To identify genes regulated by short-term IL-6 treatment, we performed RNAseq profiling of naïve murine CD8+ T cells stimulated for 4 hours with recombinant mouse IL-6 in the presence or absence of anti-CD3/CD28 antibodies. We found that IL-6 controls expression of diverse regulators of T cell differentiation and function, including repression of co-stimulatory receptors, induction of co-inhibitory receptors, and induction of transcription factors important for memory formation and T cell quiescence.

ORGANISM(S): Mus musculus

PROVIDER: GSE199045 | GEO | 2022/11/04

REPOSITORIES: GEO

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Optimized delivery of dual co-stimulation and anti-tumor activity using parallel chimeric antigen receptors (pCARs)

Project description:Second generation (2G) chimeric antigen receptors (CARs) contain a CD28 or 41BB co-stimulatory endodomain and elicit remarkable efficacy in hematological malignancies. Third generation (3G) CARs extend this linear blueprint by fusing both co-stimulatory units in series. However, clinical impact has been muted despite compelling evidence that co-signaling by CD28 and 41BB can powerfully amplify natural immune responses. We postulate that effective dual co-stimulation requires juxta-membrane positioning of endodomain components within separate synthetic receptors. Consequently, we designed parallel (p)CARs in which a 2G (CD28+CD3) CAR is co-expressed with a 41BB-containing chimeric co-stimulatory receptor. We demonstrate that the pCAR platform optimally harnesses synergistic and tumor-dependent co-stimulation to resist T-cell exhaustion and senescence, sustaining proliferation, cytokine release, cytokine signaling and metabolic fitness upon repeated stimulation. When engineered using targeting moieties of diverse composition, affinity and specificity, pCAR T-cells consistently elicit superior anti-tumor activity both in vitro and in vivo, warranting clinical development.

2021-12-10 | GSE186557 | GEO

Raptor/mTORC1-dependent metabolic programming of exit from quiescence underlies T cell activation and fate decisions

Project description:Naïve T cells respond to antigen stimulation by exiting from quiescence into clonal expansion and functional differentiation, but the control mechanism is elusive. Here we describe that Raptor/mTORC1-dependent metabolic reprogramming is a central determinant of this transitional process. Loss of Raptor abrogates T cell priming and Th2 cell differentiation, although Raptor function is less important for continuous proliferation of actively cycling cells. mTORC1 coordinates multiple metabolic programs in T cells including glycolysis, lipid synthesis and oxidative phosphorylation to mediate antigen-triggered exit from quiescence. mTORC1 further links glucose metabolism to the initiation of Th2 differentiation by orchestrating cytokine receptor expression and cytokine responsiveness. Activation of Raptor/mTORC1 integrates T cell receptor (TCR) and CD28 co-stimulatory signals in antigen-stimulated T cells. Our studies identify a Raptor/mTORC1-dependent pathway linking signal-dependent metabolic reprogramming to quiescence exit, and this in turn coordinates lymphocyte activation and fate decisions in adaptive immunity. We used microarrays to explore the gene expression profiles differentially expressed in CD4+ T-cells from wild-type (WT) and CD4(cre) x Raptor(fl/fl) mice before and after stimulation with anti CD3/CD28 antibodies.

2014-01-27 | E-GEOD-51668 | biostudies-arrayexpress

Profiling of Jurkat T cells activated with CD3, CD28 and PMA at 1 and 8 hours

Project description:T lymphocytes are orchestrators of adaptive immunity. Naïve T cells may differentiate into the Th1, Th2, Th17 or iTreg phenotype, depending on environmental co-stimulatory signals. In order to identify the genes and pathways involved in differentiation of Jurkat T cells towards Th1 and Th2 subtypes we performed comprehensive transcriptome analyses of Jurkat T cells stimulated with various stimuli an pathway inhibitors Jurkat T cells were treated with CD3/CD28 and CD3/PMA and CD28/PMA. RNA was isolated after 1 and 8 hrs stumalation.

2011-07-15 | E-GEOD-30676 | biostudies-arrayexpress

Gene expression profile of conventional T cells (Tconv) and regulatory T cells (Treg) stimulated with anti-costimulatory molecule antibodies

Project description:Co-stimulatory molecules of the CD28 family on T lymphocytes integrate cues from innate immune system sensors, and modulate activation responses in conventional CD4+ T cells (Tconv) and their FoxP3+ regulatory counterparts (Treg). To better understand how costimulatory and co-inhibitory signals might be integrated, we profiled the changes in gene expression elicited in the hours and days after engagement of Treg and Tconv by anti-CD3 and either anti-CD28, -CTLA4, -ICOS, -PD1, -BTLA or -CD80.

2012-11-15 | GSE42276 | GEO

RNA-seq profiling of in vitro FRC-conditioned, IL6-conditioned or control (anti-CD3/CD28)-stimulated CD8+ T cells

Project description:To broadly assess which pathways FRCs regulate in CD8+ T cells, we sorted CD8+ T cells for RNA-seq following activation in whole splenocyte mixtures via soluble anti-CD3/CD28 for 48 hours (Stim), activated with anti-CD3/CD28 in the presence of Nos2–/– FRCs (FRC) or activated with anti-CD3/CD28 plus 100 ng/ml recombinant IL-6 (IL-6). Here we demonstrate that FRC-derived signals, including IL-6, act in concert with TCR signaling and co-stimulation to promote the expression of MYC and HIF-1-dependent glycolytic genes and vital pro-survival genes (encoding BCL-2 family members, inhibitors of apoptosis [IAPs] members and Cflar) in activated CD8+ T cells.

2019-10-14 | GSE136898 | GEO

Transcription profiling of mouse Itk-deficiency using CD3+ T-cells

Project description:The Tec-family kinase Itk plays an important role during T-cell activation and function, and controls also conventional versus innate-like T-cell development. We have characterized the transcriptome of Itk-deficient CD3+ T-cells, including CD4+ and CD8+ subsets, using Affymetrix microarrays. The largest difference between Itk-/- and Wt CD3+ T-cells was found in unstimulated cells, e.g. for killer cell lectin-like receptors. Compared to anti-CD3-stimulation, anti-CD3/CD28 significantly decreased the number of transcripts suggesting that the CD28 co-stimulatory pathway is mainly independent of Itk. The signatures of CD4+ and CD8+ T-cell subsets identified a greater differential expression than in total CD3+ cells. Cyclosporin (CsA)-treatment had a stronger effect on transcriptional regulation than Itk-deficiency, suggesting that only a fraction of TCR-mediated calcineurin/NFAT-activation is dependent on Itk. Bioinformatic analysis of NFAT-sites of the group of transcripts similarly regulated by Itk-deficiency and CsA-treatment, followed by chromatin-immunoprecipitation, revealed NFATc1-binding to the Bub1, IL7R, Ctla2a, Ctla2b, and Schlafen1 genes. Finally, to identify transcripts that are regulated by Tec-family kinases in general, we compared the expression profile of Itk-deficient T-cells with that of Btk-deficient B-cells and a common set of transcripts was found. Taken together, our study provides a general overview about the global transcriptional changes in the absence of Itk. Experiment Overall Design: CD3+ T-cells from pooled suspensions of spleen and lymph nodes of Wt and Itk knockout mice on C57BL/6 background were isolated after negative depletion. Unstimulated as well as stimulated T-cells were studied. Stimulations were done with anti-CD3 (1 mg/ml) with or without anti-CD28 (3 mg/ml) in the presence or absence of CsA (1 mg/ml) for 24 hrs. For each stimulus, at least duplicate samples were used.

2009-05-29 | E-GEOD-12464 | biostudies-arrayexpress

Expression data from mouse CD19-targeted CAR (chimeric antigen receptor) T cells after antigen stimulation [expression array]

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2018-07-31 | GSE111641 | GEO

Expression data from mouse CD19-targeted CAR (chimeric antigen receptor) T cells after antigen stimulation [RNA-seq]

2018-07-31 | GSE112566 | GEO

ATAC-seq profiling of in vitro FRC-conditioned, IL6-conditioned or control (anti-CD3/CD28)-stimulated CD8+ T cells

Project description:To broadly assess which pathways FRCs regulate in CD8+ T cells, we sorted CD8+ T cells for ATAC-seq following activation in whole splenocyte mixtures via soluble anti-CD3/CD28 (0.25μg/ml) for 48 hours (Stim), activated with anti-CD3/CD28 in the presence of Nos2–/– FRCs (FRC) or activated with anti-CD3/CD28 plus 100 ng/ml recombinant IL-6 (IL-6). Here we demonstrate that FRC-derived signals, including IL-6, act in concert with TCR signaling and co-stimulation to remodel chromatin and render essential transcription factor binding motifs accessible in activated CD8+ T cells. Signals from FRCs led to increased binding regions for MYC, HIF-1α and HIF-1β, which are known to promote metabolic pathways following T cell activation. Additionally, FRC-derived signals promoted activity of transcription factors that regulate survival and memory programs in T lymphocytes such as BATF and BACH2.

2019-10-14 | GSE136903 | GEO

Transcriptional signatures of Itk-deficiency using CD3+, CD4+ and CD8+ T-cells

2009-05-20 | GSE12465 | GEO

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