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Antigen-driven EGR2 expression is required for exhausted CD8+ T cell stability and maintenance [CHIP-seq]

ABSTRACT: In this study, we examined the role of the transcriptional regulator EGR2 in CD8+ T cell exhaustion during chronic viral infection. Flow cytometric and RNAseq analysis indicated that EGR2 deficient CD8+ T cells had a block in differentiation and failed to undergo terminal exhaustion. To examine the direct gene targets of EGR2 during exhaustion, we conducted ChIPseq analysis on enriched bulk splenic CD8+ T cells isolated at day 20 post-infection with chronic LCMV-Cl13 from C57BL/6J mice. The resulting data demonstrated that EGR2 directly controls expression of key gene targets, including Pdcd1, Tigit, Cxcr5, Tcf7, Bach2 and Bcl6.

ORGANISM(S): Mus musculus

PROVIDER: GSE134708 | GEO | 2021/03/02

REPOSITORIES: GEO

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Antigen-driven EGR2 expression is required for exhausted CD8+ T cell stability and maintenance [RNA-seq I]

Project description:In this study, we examined the role of the transcriptional regulator EGR2 in CD8+ T cell exhaustion during chronic viral infection. Flow cytometric analysis indicated that EGR2 deficient CD8+ T cells had a block in differentiation and failed to undergo terminal exhaustion. To confirm this at a whole transcriptome level, we conducted RNAseq analysis on sorted splenic virus-specific tetramer+ CD8+ T cells isolated at day 20 post-infection with chronic LCMV-Cl13 from either littermate control or EGR2 T cell conditional knock-out mice. The resulting data demonstrated that there was a global loss of the terminally exhausted gene signature within EGR2 KO CD8+ T cells. This suggests that EGR2 promotes terminal CD8+ T cell exhaustion.

2021-03-02 | GSE134689 | GEO

Antigen-driven EGR2 expression is required for exhausted CD8+ T cell stability and maintenance [scRNAseq]

Project description:In this study, we examined the role of the transcriptional regulator EGR2 in CD8+ T cell exhaustion during chronic viral infection. We conducted scRNAseq analysis on sorted virus-specific tetramer+ CD8+ T cells isolated at day 20 post-infection with chronic LCMV-Cl13 from either littermate control or EGR2 T cell conditional knock-out mice. Cells were labelled with hashtags and mixed prior to multiplexed analysis. The resulting data demonstrated that the exhausted cell subsets within EGR2 KO CD8+ T cells have an effector-like phenotype, suggesting that EGR2 stabilises the exhausted state.

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Antigen-driven EGR2 expression is required for exhausted CD8+ T cell stability and maintenance [ATACseq]

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2021-03-02 | GSE153136 | GEO

Antigen-driven EGR2 expression is required for exhausted CD8+ T cell stability and maintenance [RNA-seq II]

Project description:In this study, we examined the role of the transcriptional regulator EGR2 in CD8+ T cell exhaustion during chronic viral infection. Flow cytometric analysis indicated that EGR2 is expressed selectively within the progenitor exhausted subset, however a subpopulation of progenitor exhausted cells did not express in EGR2. To define the differences between the EGR2+ and EGR2- progenitor exhausted cells, GFP+ and GFP- polyclonal progenitor exhausted (ie. CD44int-hiPD-1+Slamf6+Tim3-) CD8+ T cells were sorted from Egr2-GFP reporter mice at day 20 p.i. with chronic LCMV-Cl13, and analysed by RNAseq. The resulting data demonstrated that GFP- progenitor cells have a more differentiated phenotype.

2021-03-02 | GSE152849 | GEO

AAV-HBV mouse model shows similar exhaustion marker pattern to chronic HBV patients at single-cell level.

Project description:Background and Aims: Unresolved hepatitis B virus (HBV) infection leads to a progressive state of immune exhaustion that impairs resolution of infection, leading to chronic infection (CHB). The immune-competent AAV-HBV mouse is a common HBV preclinical immune competent model, though a comprehensive characterization of the liver immune microenvironment and its translatability to human infection is still lacking. We investigated the intrahepatic immune profile of the AAV-HBV mouse model at a single-cell level and compared with data from CHB patients in immune tolerant (IT) and immune active (IA) clinical stages. Methods: Immune exhaustion was profiled through an iterative subclustering approach for cell-typing analyses of single-cell RNA-sequencing data in CHB donors and compared to the AAV-HBV mouse model 24-weeks post-transduction to assess its translatability. This was validated using an exhaustion flow cytometry panel at 40 weeks post-transduction. Results: Using single-cell RNA-sequencing, CD8 pre-exhausted T-cells with self-renewing capacity (TCF7+), and terminally exhausted CD8 T-cells (TCF7-) were detected in the AAV-HBV model. These terminally exhausted CD8 T-cells (expressing Pdcd1, Tox, Lag3, Tigit) were significantly enriched versus control mice and independently identified through flow cytometry. Importantly, comparison to CHB human data showed a similar exhausted CD8 T-cell population in IT and IA donors, but not in uninfected individuals. Conclusions: Long term high titer AAV-HBV mouse liver transduction led to T-cell exhaustion, as evidenced by expression of classical immune checkpoint markers at mRNA and protein levels. In both IT and IA donors, a similar CD8 exhausted T-cell population was identified, with increased frequency observed in IA donors. These data support the use of the AAV-HBV mouse model to study T-cell exhaustion in HBV infection and the effect of immune-based therapeutic interventions.

2024-12-31 | GSE244487 | GEO

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Project description:Transcription profiling of mouse FR4+Egr2+, FR4+Egr2- and FR4-Egr2- CD4+ T cells extracted from GFP-Egr2 knockin (Egr2 Kin) and FR4+Egr2-/-Egr3-/- and FR4-Egr2-/-Egr3-/- CD4+ T cells isolated from Egr2loxP/loxP hCD2-Cre Egr3-/- (Egr2/3 DKO) mice in the steady state or 21 days after infection with vaccinia virus.

2025-01-01 | E-MTAB-12736 | biostudies-arrayexpress

RNA-seq analysis of CD8 tumour infiltrating lymphocytes from GFP-Egr2 Knockin and hCD2-Cre Egr2loxP/loxP Egr3-/- mice

Project description:To determine the effect of Egr2 and Egr3 on tumour infiltrating lymphocyte gene expression, GFP-Egr2 knockin (Egr2 Kin) and hCD2-Cre Egr2loxP/loxP Egr3-/- (Egr2/3 DKO) mice were inoculated with MC38 or B16 tumour cells. Fourteen days later, GFP-Egr2high and Egr2-/-Egr3-/- CD8+ tumour infiltrating lymphocytes were isolated from Egr2 Kin and Egr2/3 DKO mice, respectively, and analysed by RNA-seq.

2023-01-31 | E-MTAB-11672 | biostudies-arrayexpress

TIGIT expression on CD8+ T cells correlates with higher cytotoxic capacity

Project description:Persistent exposure to antigen leads to T cell exhaustion and immunologic dysfunction. We examined the immune exhaustion markers TIGIT and PD-1 in HIV-infected and healthy individuals and the relationship with cytotoxic CD8+ T lymphocyte (CTL) activity. Frequencies of TIGIT but not PD-1 positively correlated with CTL activity in HIV-aviremic and healthy individuals; however, there was no correlation in HIV-viremic individuals. Transcriptome analyses revealed upregulation of genes associated with antiviral immunity in TIGIT+ versus TIGIT-CD8+ T cells. Our data suggest that TIGIT+CD8+ T cells do not necessarily represent a state of immune exhaustion and maintain an intrinsic cytotoxicity in HIV-infected individuals.

2021-03-31 | GSE171172 | GEO

RNA-seq of LCMV GP33-specific CD8 TCR transgenic cells (P14) primed at the onset versus in the midst of persistent LCMV-Clone 13 viral infection

Project description:Altered CD8 T cell differentiation and functional exhaustion prevent control of chronic virus infection and cancer. Yet, how fate commitment and exhaustion are determined and dynamically modulated throughout persistent infection are unclear. We compared the activation and differentiation of LCMV GP33-specific CD8 TCR transgenic cells (P14) primed at the onset versus in the midst of established persistent LCMV-Clone 13 viral infection. LCMV GP33-specific CD8 TCR transgenic (P14) cells were injected into naïve mice immediately infected with LCMV-Cl13 (Early priming) or into mice that had been infected 21 days earlier with LCMV-Cl13 (Late Priming). Sixty hours post-priming P14 cells were sorted from mice and subjected to RNA seq. We show early primed cells very rapidly exhibit a transcriptional profile of robust activation, effector differentiation and dysfunction, while late primed cells have increased expression of genes involved in memory differentiation and maintenance.

2018-10-09 | GSE105044 | GEO

BACH2 Establishes the Transcriptional and Epigenetic Programs of Stem-Like CD8 T cells

Project description:During chronic infection and cancer, a self-renewing CD8 T cell subset maintains long-term T-cell immunity and mediate the response induced by immunotherapy. These stem-like CD8 T cells diverge from other CD8 subsets early in the immune response and display distinct transcriptional and epigenetic signatures. Here, we show that locus encoding transcriptional factor BACH2 is transcriptionally and epigenetically active in stem-like CD8 T cells but not in terminally exhausted CD8 T cells. Overexpression of BACH2 enforces the stem-like cell fate, whereas Bach2 deficiency impairs stem-like CD8 T cell differentiation. Using single-cell transcriptomics and epigenomics approaches, we demonstrate BACH2 as a key regulator of the transcriptional and epigenetic programs of stem-like CD8 T cells. In addition, BACH2 suppresses genes and pathways that drive terminal exhaustion through transcriptional repression and epigenetic silencing. Thus, our study reveals a novel pathway responsible for establishing the unique transcriptional and epigenetic program of stem-like CD8 T cells.

2020-12-14 | GSE152379 | GEO

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