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Krüppel-like factor 4 regulates the cytolytic effector function of exhausted CD8 T-cells [ATAC-Seq]

ABSTRACT: Since exhausted CD8 T-cells are known to have a strong epigenetic imprint, which is a major obstacle for reinvigoration, we investigated whether the induced Klf4 expression could change the epigenetic status of the exhausted CD8 T-cells. For this, we performed ATAC-sequencing and compared chromatin landscapes between naïve, in vitro generated effector, exhausted (GFP-induced), and reinvigorated (KLF4-induced) CD8 T-cells.

ORGANISM(S): Mus musculus

PROVIDER: GSE212805 | GEO | 2022/10/24

REPOSITORIES: GEO

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Krüppel-like factor 4 regulates the cytolytic effector function of exhausted CD8 T-cells [SMART-Seq]

Project description:To identify the role of KLF4 on exhausted CD8 T-cells in vivo, we adoptively transferred PmelI CD8 T-cells transduced with MigRI/Klf4 into MC38-gp100 tumor-bearing Rag2 KO mice on day7. We then isolated tumor-infiltrating PmelI CD8 T-cells on day15 and their gene expression profiles were analyzed by SMART-seq. Also, to investigate the effect of KLF4 deficiency, we isolated PD1+ CD8+ TILs from MC38 tumor-bearing control and Klf4 cKO mice on day14, and SMART-seq was performed.

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Krüppel-like factor 4 regulates the cytolytic effector function of exhausted CD8 T-cells [RNA-Seq]

Project description:To identify the role of KLF4 on exhausted CD8 T-cells, we retrovirally transduced Klf4 into OT-I CD8 T-cells on day1 of in vitro exhaustion model and repeatedly treated OVA peptide to induce exhaustion. Then we analyzed the gene expression profiles of these transduced cells by RNA-sequencing.

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4-1BB Co-stimulation Further Enhances Anti-PD-1-Mediated Reinvigoration of Exhausted CD39+ CD8 T Cells from Primary and Metastatic sites of Epithelial Ovarian Cancers

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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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Transcription profiling of mouse naive, effector, memory and exhausted virus-specific CD8 T cells after chronic viral infection

Project description:CD8 T cells normally differentiate from resting naÃ¯ve 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.

2008-06-16 | E-GEOD-9650 | biostudies-arrayexpress

PD-1 blockade-unresponsive human tumor-infiltrating CD8+ T cells are marked by loss of CD28 expression and rescued by IL-15

Project description:Blockade of programmed death-1 (PD-1) reinvigorates exhausted CD8+ T cells, resulting in tumor regression in cancer patients. Recently, reinvigoration of exhausted CD8+ T cells following PD-1 blockade was shown to be CD28-dependent in mouse models. Herein, we examined the role of CD28 in anti-PD-1-induced human T-cell reinvigoration using tumor-infiltrating CD8+ T cells (CD8+ TILs) obtained from non-small cell lung cancer patients. Single cell analysis demonstrated a distinct expression pattern of CD28 between mouse and human CD8+ TILs. Furthermore, we found that human CD28+CD8+, but not CD28–CD8+ TILs, responded to PD-1 blockade irrespective of B7/CD28 blockade, indicating that CD28 co-stimulation in human CD8+ TILs is dispensable for PD-1 blockade-induced reinvigoration, and loss of CD28 expression rather serve as a marker of anti-PD-1-unresponsive CD8+ TILs. Transcriptionally and phenotypically, PD-1 blockade-unresponsive human CD28–PD-1+CD8+ TILs exhibited characteristics of terminally exhausted CD8+ T cells with low TCF1 expression. Notably, CD28–PD-1+CD8+ TILs had preserved machinery to respond to IL-15, and IL-15 treatment enhanced proliferation of CD28–PD-1+CD8+ TILs as well as CD28+PD-1+CD8+ TILs. Taken together, we demonstrate loss of CD28 expression as a marker of PD-1 blockade-unresponsive human CD8+ TILs with TCF1– signature and provide mechanistic insights into combining IL-15 with anti-PD-1.

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2015-09-08 | E-GEOD-72752 | biostudies-arrayexpress

RNA-sequencing of ex vivo exhausted human antigen-specific T cells

| EGAS00001006794 | EGA

Single-cell RNA-seq of human breast tumor samples with exhausted and non-exhausted immune environments

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2023-08-25 | E-MTAB-10607 | biostudies-arrayexpress

Mechanisms of Restoring T Cell Immunity after Cure of Chronic Viral Infection

Project description:Understanding the molecular mechanisms of T cell exhaustion and reinvigoration is crucial to improving T cell based immunotherapy. In this study we confirmed key differences between memory and exhausted antigen-specific CD8+ T cells in hepatitis C virus infection before and after antiviral treatment. After viral cure, we observed the although phenotypically they seem to recover, functionally they showed little improvement and critical transcriptional regulators remained in exhausted state.

2022-09-08 | GSE212871 | GEO

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