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Dynamic CD4 T cell heterogeneity defines subset-specific suppression and PDL1-blockade driven functional restoration in chronic infection [Bulk-seq]

ABSTRACT: Dynamic CD4 T cell heterogeneity defines subset-specific suppression and PDL1-blockade driven functional restoration in chronic infection [Bulk-seq]

PROVIDER: PRJNA685429 | ENA |

REPOSITORIES: ENA

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Dynamic CD4 T cell heterogeneity defines subset-specific suppression and PDL1-blockade driven functional restoration in chronic infection [Bulk-seq]

Project description:Inhibiting PD1:PDL1 signaling has transformed therapeutic immune restoration. CD4 T cells are critical to sustain immunity in chronic infections and cancer, yet little is known about how PD1/L1 modulates CD4 T helper (Th) responses or the ability to restore CD4 Th-mediated immunity by inhibiting PD1/L1 signaling. We demonstrate that PD1/L1 specifically suppresses CD4 Th1 cell amplification, prevents CD4 Th1 cytokine production, and abolishes CD4 CTL killing capacity during chronic infection. Inhibiting PDL1 during chronic infection rapidly restored these functions, while simultaneously enhancing Th1-like Treg amplification and activation, indicating a system-wide CD4-Th1 recalibration. Paradoxically, PDL1-blockade decreased TCR signaling, while re-directing intrinsically-suppressive type I interferon networks towards dominant IFNγ-mediated responses. Mechanistically, PDL1-blockade specifically targeted defined populations with pre-established, but actively-suppressed proliferative potential, with limited impact on minimally-cycling TCF1+ Tfh, despite high PD1 expression. Thus, CD4 T cells require unique differentiation and functional states to be targets of PDL1-directed suppression and therapeutic restoration.

2021-09-20 | GSE163259 | GEO

Dynamic CD4 T cell heterogeneity defines subset-specific suppression and PDL1-blockade driven functional restoration in chronic infection [scRNA-seq]

2021-09-20 | GSE163343 | GEO

Dynamic CD4 T cell heterogeneity defines subset-specific suppression and PDL1-blockade driven functional restoration in chronic infection

Project description:Dynamic CD4 T cell heterogeneity defines subset-specific suppression and PDL1-blockade driven functional restoration in chronic infection

| PRJNA685775 | ENA

Dynamic CD4 T cell heterogeneity defines subset-specific suppression and PDL1-blockade driven functional restoration in chronic infection [scRNA-seq]

Project description:Dynamic CD4 T cell heterogeneity defines subset-specific suppression and PDL1-blockade driven functional restoration in chronic infection [scRNA-seq]

| PRJNA685782 | ENA

Dynamic CD4 T cell heterogeneity defines subset-specific suppression and PDL1-blockade driven functional restoration in chronic infection

Project description:This SuperSeries is composed of the SubSeries listed below.

2021-09-20 | GSE163345 | GEO

Smart-seq II Sequencing Analysis of Pdl1+ and Pdl1- mammary gland basal cell Transcriptomes

Project description:Purpose:Smart sequencing (NGS) has revolutionized systems-based analysis of cellular pathways. The goals of this study are to compare gene expression of Pdl1+ and Pdl1- mammary gland basal cell analysis.Methods:Pdl1+ and Pdl1- mammary gland basal cell mRNA profiles of wild-type (WT) were generated by deep sequencing, in triplicate, using Illumina nova seq. The sequence reads that passed quality filters were analyzed at the transcript isoform level with two methods: Hisat2 as the mapping tool followed byDESeq R package. qRT–PCR validation was performed using TaqMan and SYBR Green assays.Results: Using an optimized data analysis workflow, RNA-seq data confirmed and validated with qRT–PCR.

2021-02-04 | GSE166131 | GEO

Combination therapy with nilotinib and PDL1 blockade reverses CD4 T cell dysfunction and prevents relapse in acute B cell leukemia

Project description:Patients with acute lymphoblastic leukemia have experienced significantly improved outcomes due to the advent of chimeric antigen receptor T-cells and bispecific T-cell engagers, although a proportion of patients still relapse despite these advances. T cell exhaustion has been recently suggested to be an important driver of relapse in these patients. Indeed, phenotypic exhaustion of CD4+ T-cells are predictive of relapse and poor overall survival in B-ALL. Thus, therapies that counter T cell exhaustion, such as immune checkpoint blockade, may improve leukemia immunosurveillance and prevent relapse. Here, we used a murine model of Ph+ B-ALL as well as human bone marrow biopsy samples to assess the fundamental nature of CD4+ T-cell exhaustion and the preclinical therapeutic potential for combining anti-PDL1 based checkpoint blockade with tyrosine kinase inhibitors targeting the BCR-ABL oncoprotein. scRNA-seq analysis revealed that B-ALL induces a unique subset of CD4+ T-cells with both cytotoxic and helper functions. Combination treatment with the tyrosine kinase inhibitor nilotinib and anti-PDL1 dramatically improves long-term survival of leukemic mice. Depletion of CD4 T cells prior to therapy completely abrogates the survival benefit, implicating CD4 T cells as key drivers of the protective anti-leukemia immune response. Indeed, treatment with anti-PDL1 leads to clonal expansion of leukemia-specific CD4 T cells with the afore-mentioned cytotoxic/helper phenotype, as well as reduced expression of exhaustion markers. These findings support efforts to utilize PD1/PD-L1 checkpoint blockade in clinical trials and highlight the importance of CD4+ T-cell dysfunction in limiting the endogenous anti-leukemia response.

2022-07-15 | GSE195964 | GEO

LC-MS/MS Proteomics analysis of PDL1 protein in 293T cell line

Project description:To identify the proteins interact with PDL1 protein in human cell lines, we analyzed the protein complexes using tandem affinity purification followed by mass spectrometry (TAP-MS) in HEK293T. We established the cell lines stably expressing PDL1 gene fused with Flag tags. We identified proteins associated with the bait in the isolated complexes using MS and searched the human databases for these proteins.

2022-10-13 | PXD031702 | Pride

Stage-specific sensitivity to p53 restoration in lung cancer

Project description:This SuperSeries is composed of the following subset Series: GSE23873: Stage-specific sensitivity to p53 restoration in lung cancer: cell line data GSE23874: Stage-specific sensitivity to p53 restoration in lung cancer: tumor data Refer to individual Series

2010-11-24 | E-GEOD-23875 | biostudies-arrayexpress

VHL restoration alters cis-regulatory landscape

Project description:VHL loss is the most common genetic alteration event in ccRCC. By profiling histone modifications from VHL-deficient ccRCC primary tumors and cell lines, we identifed tumor-associated promoters and enhancers. We next investigate whether VHL restoration alters tumor associated promoters and enhancers. We compared H3K27ac ChIP-seq with and without VHL restoration in 786-O cells. Restoration of wild-type VHL significantly altered a subset of tumor enhancers but affected promoters to a less extent.

2017-08-22 | GSE102095 | GEO

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