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Single-Cell Transcriptomics Identifies TOX as a Key Transcriptional Regulator of Progenitor-Like CD8 T Cells in Chronic Infection [single-cell RNA-seq]

ABSTRACT: Stem-like CD8 T cells maintain long-term antiviral CD8 immunity during chronic infection, and share regulatory pathways with memory precursor effector cells generated after acute infection. However, it is unclear whether stem-like CD8 T cells require dist

ORGANISM(S): Mus musculus

PROVIDER: GSE119940 | GEO | 2019/04/16

REPOSITORIES: GEO

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Single-Cell Transcriptomics Identifies TOX as a Key Transcriptional Regulator of Progenitor-Like CD8 T Cells in Chronic Infection [RNA-seq]

Project description:Stem-like CD8 T cells maintain long-term antiviral CD8 immunity during chronic infection, and share regulatory pathways with memory precursor effector cells generated after acute infection. However, it is unclear whether stem-like CD8 T cells require distinct transcriptional and epigenetic regulation for their longevity and adaptation to the immunosuppressive environment in chronic infection. Here, our comparison of single-cell transcriptomes and epigenetic profiles of CD8 T cells responding to acute and chronic viral infections revealed that stem-like CD8 T cells became distinct from memory precursors before clonal expansion ended. We found that a coexpression gene module containing Tox exhibited higher transcriptional activities and active histone marks in stem-like T cells than memory precursors. Moreover, TOX promoted persistence of antiviral CD8 T cells, and was required for stem-like CD8 differentiation. Our results indicate that stem-like CD8 T cells require unique transcriptional and epigenetic programs for their differentiation and persistence during chronic viral infection.

2019-04-16 | GSE119942 | GEO

Single-Cell Transcriptomics Identifies TOX as a Key Transcriptional Regulator of Progenitor-Like CD8 T Cells in Chronic Infection [ChIP-seq]

2019-04-16 | GSE119941 | GEO

Single-cell RNA-seq reveals TOX as a key regulator of CD8<sup>+</sup> T cell persistence in chronic infection.

Project description:Progenitor-like CD8+ T cells mediate long-term immunity to chronic infection and cancer and respond potently to immune checkpoint blockade. These cells share transcriptional regulators with memory precursor cells, including T cell-specific transcription factor 1 (TCF1), but it is unclear whether they adopt distinct programs to adapt to the immunosuppressive environment. By comparing the single-cell transcriptomes and epigenetic profiles of CD8+ T cells responding to acute and chronic viral infections, we found that progenitor-like CD8+ T cells became distinct from memory precursor cells before the peak of the T cell response. We discovered a coexpression gene module containing Tox that exhibited higher transcriptional activity associated with more abundant active histone marks in progenitor-like cells than memory precursor cells. Moreover, thymocyte selection-associated high mobility group box protein TOX (TOX) promoted the persistence of antiviral CD8+ T cells and was required for the programming of progenitor-like CD8+ T cells. Thus, long-term CD8+ T cell immunity to chronic viral infection requires unique transcriptional and epigenetic programs associated with the transcription factor TOX.

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Single-Cell Transcriptomics Identifies TOX as a Key Transcriptional Regulator of Progenitor-Like CD8 T Cells in Chronic Infection

Project description:Single-Cell Transcriptomics Identifies TOX as a Key Transcriptional Regulator of Progenitor-Like CD8 T Cells in Chronic Infection

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Small molecule endoplasmic reticulum proteostasis regulator acts as a broad-spectrum inhibitor of Dengue and Zika virus infections

Project description:Flaviviruses, including Dengue and Zika, are widespread human pathogens; however, no broadly active therapeutics exist to fight infection. Recently, remodeling of endoplasmic reticulum (ER) proteostasis by pharmacologic regulators, such as compound 147, was shown to correct pathologic ER imbalances associated with protein misfolding diseases. Here, we establish a new activity of compound 147 as an effective host-centered antiviral agent against flaviviruses. Compound 147 reduces infection by attenuating the infectivity of secreted virions without causing toxicity in host cells. 147 is a preferential activator of the ATF6 pathway of the ER unfolded protein response, which requires targeting of cysteine residues primarily on protein disulfide isomerases (PDIs). We find that the antiviral activity of 147 is independent of ATF6 induction but does require modification of reactive thiols on protein targets. Targeting PDIs and additional non-PDI targets using RNAi and other small molecule inhibitors was unable to recapitulate the antiviral effects, suggesting a unique polypharmacology may mediate the activity. Importantly, 147 can impair infection of multiple strains of Dengue and Zika virus, indicating that it is suitable as a broad-spectrum antiviral agent.

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Gene expression profile at single cell level of virus-specific CD8+ T cells in subjects with past or current HCV infection.

Project description:CD8+ T cells play a central role in antiviral control. We used single cell RNA sequencing (scRNA-seq) to analyze the differences of HCV-specific CD8+ T cells isolated from subjects that are chronically infected by HCV, individuals that spontaneously resolved an acute HCV infection, and chronic HCV patients in treatment with direct-acting antiviral (DAA). We also profiled non-HCV virus-specific cells (CMV and FLU) to analyze the impact of HCV infection on the adaptive immune response.

2023-06-08 | GSE228763 | GEO

TOX Transcriptionally and Epigenetically Programs CD8 T cell Exhaustion [WT vs TOX-KO RNA-Seq]

Project description:Transcriptional and epigenetic features were detected in WT versus TOX-/- P14 T cells following 8 days of Cl-13 infection and in in vitro differentiated CD8 T cells or NIH3T3 fibroblasts following retroviral transduction with control or TOX

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TOX Transcriptionally and Epigenetically Programs CD8 T cell Exhaustion [CT vs TOX RNA-Seq CD8]

2019-06-19 | GSE132984 | GEO

TOX Transcriptionally and Epigenetically Programs CD8 T cell Exhaustion [CT vs TOX ATAC-Seq CD8]

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TOX Transcriptionally and Epigenetically Programs CD8 T cell Exhaustion [WT vs TOX-KO ATAC-Seq]

2019-06-19 | GSE132986 | GEO