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ScRNA-seq for “HDAC1 controls the generation and maintenance of effector-like CD8+ T cells during chronic viral infection”

ABSTRACT: CD8+ T cell exhaustion is a complex process involving the differentiation of persistently activated CD8+ T cells into functionally distinct cell subsets. Here, we investigated the role of the key epigenetic regulator histone deacetylase 1 (HDAC1) in the differentiation of exhausted T (Tex) cells during chronic viral infection. We uncovered that HDAC1 controls the generation and maintenance of effector-like CX3CR1+ Tex cells in a CD8+ T cell-intrinsic manner. Deletion of HDAC1 led to expansion of an alternative Tex subset characterized by high expression of T cell exhaustion markers, and this was accompanied by elevated viremia. HDAC1 bound to and facilitated an open chromatin state of effector-like signature gene loci in progenitor Tex cells, thereby priming cell fate specification toward the CX3CR1+ Tex subset. Our study un-covers a selective role for HDAC1 in CX3CR1+ Tex subset differentiation, which is essential for controlling viral load during chronic infection.

ORGANISM(S): Mus musculus

PROVIDER: GSE255886 | GEO | 2025/05/22

REPOSITORIES: GEO

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ATAC-seq for “HDAC1 controls the generation and maintenance of effector-like CD8+ T cells during chronic viral infection”

Project description:CD8+ T cell exhaustion is a complex process involving the differentiation of persistently activated CD8+ T cells into functionally distinct cell subsets. Here, we investigated the role of the key epigenetic regulator histone deacetylase 1 (HDAC1) in the differentiation of exhausted T (Tex) cells during chronic viral infection. We uncovered that HDAC1 controls the generation and maintenance of effector-like CX3CR1+ Tex cells in a CD8+ T cell-intrinsic manner. Deletion of HDAC1 led to expansion of an alternative Tex subset characterized by high expression of T cell exhaustion markers, and this was accompanied by elevated viremia. HDAC1 bound to and facilitated an open chromatin state of effector-like signature gene loci in progenitor Tex cells, thereby priming cell fate specification toward the CX3CR1+ Tex subset. Our study un-covers a selective role for HDAC1 in CX3CR1+ Tex subset differentiation, which is essential for controlling viral load during chronic infection.

2025-05-22 | GSE255884 | GEO

CUT&RUN for “HDAC1 controls the generation and maintenance of effector-like CD8+ T cells during chronic viral infection”

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HDAC1 controls the generation and maintenance of effector-like CD8+ T cells during chronic viral infection

Project description:CD8+ T cell exhaustion is a complex process involving the differentiation of persistently acti-vated CD8+ T cells into functionally distinct cell subsets. Here, we investigated the role of the key epigenetic regulator histone deacetylase 1 (HDAC1) in the differentiation of exhausted T (Tex) cells during chronic viral infection. We uncovered that HDAC1 controls the generation and maintenance of effector-like CX3CR1+ Tex cells in a CD8+ T cell-intrinsic manner. Dele-tion of HDAC1 led to expansion of an alternative Tex subset characterized by high expression of T cell exhaustion markers, and this was accompanied by elevated viremia. HDAC1 bound to and facilitated an open chromatin state of effector-like signature gene loci in progenitor Tex cells, thereby priming cell fate specification toward the CX3CR1+ Tex subset. Our study un-covers a selective role for HDAC1 in CX3CR1+ Tex subset differentiation, which is essential for controlling viral load during chronic infection.

2025-05-22 | GSE255887 | GEO

The pseudokinase Trib1 regulates the transition of exhausted T cells to a KLR+ CD8+ effector state and its deletion improves checkpoint blockade

Project description:CD8+ T cell exhaustion (TEX) impairs the ability of T cells to clear chronic infection or cancer. While TEX are hypofunctional, some TEX retain effector gene signatures, a feature that is associated with expression of KLRs (killer lectin-like receptors). Although KLR+ TEX may improve control of chronic antigen, the signaling molecules regulating this population are poorly understood. Using scRNA-seq, flow cytometry, RNA velocity, and scTCR-seq, we demonstrated that deleting the pseudokinase Trib1 shifted TEX towards CX3CR1+ intermediates (TINT) with robust enrichment of KLR+ TEX (TKLR) via clonal T cell expansion. Adoptive transfer studies demonstrate this shift towards a CD8+ TKLR in Trib1 deficient cells is CD8-intrinsic, while CD4-depletion studies demonstrate that CD4+ T cells are required for optimal viral control in Trib1 conditional knockout mice. Further, Trib1 loss augmented anti-PD-L1 blockade to improve viral clearance. These data identify Trib1 as an important regulator of CD8+ TEX whose targeting enhances the TKLR effector state and improves checkpoint inhibitor therapy.

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Chromatin accessibility landscapes of CX3CR1+ effector , CX3CR1- Ly108- exhausted, or Ly108+ progenitor CD8 T cells during chronic viral infection.

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Genome-wide maps of histone modifications in CX3CR1+ effector , CX3CR1- Ly108- exhausted, or Ly108+ progenitor CD8 T cells during chronic viral infection.

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Identification of a T-bet hi Quiescent Exhausted CD8 T Cell Subpopulation That Can Differentiate into TIM3 + CX3CR1 + Effectors and Memory-like Cells

Project description:Persistent Ag induces a dysfunctional CD8 T cell state known as "exhaustion" characterized by PD-1 expression. Nevertheless, exhausted CD8 T cells retain functionality through continued differentiation of progenitor into effector cells. However, it remains ill-defined how CD8 T cell effector responses are sustained in situ. In this study, we show using the mouse chronic lymphocytic choriomeningitis virus infection model that CX3CR1+ CD8 T cells contain a T-bet-dependent TIM3-PD-1lo subpopulation that is distinct from the TIM3+CX3CR1+PD-1+ proliferative effector subset. The TIM3-CX3CR1+ cells are quiescent and express a low but significant level of the transcription factor TCF-1, demonstrating similarity to TCF-1hi progenitor CD8 T cells. Furthermore, following the resolution of lymphocytic choriomeningitis virus viremia, a substantial proportion of TCF-1+ memory-like CD8 T cells show evidence of CX3CR1 expression during the chronic phase of the infection. Our results suggest a subset of the CX3CR1+ exhausted population demonstrates progenitor-like features that support the generation of the CX3CR1+ effector pool from the TCF-1hi progenitors and contribute to the memory-like pool following the resolution of viremia.

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Distinct SWI/SNF chromatin remodelling complexes act differentially to maintain stem-like exhausted CD8 T cells [RNA-seq]

Project description:Exhausted CD8 T cells (TEX) arise during chronic viral infections and cancer and limit disease control. Three major sequential epigenetic remodeling events occur as naïve CD8 T cells (TN) differentiate into TEX: initial activation, early bifurcation between effector (TEFF) and TEX precursors, and later differentiation of effector-like and terminal TEX subsets from progenitor TEX. The epigenetic factors mediating these transitions remain poorly understood. Here, we uncovered distinct roles for two versions of the SWI/SNF chromatin remodeling complex, BAF and PBAF, in TEX differentiation using in vivo CRISPR screening. Disruption of BAF ablated antigen-specific CD8 T cells early in chronic infection, suggesting a requirement for BAF-mediated remodeling in the early epigenetic remodeling events. In contrast, depletion of PBAF subunits enhanced TEX formation and promoted progenitor TEX differentiation into more differentiated TEX subsets by limiting accessibility of TCF-1 binding sites. Loss of PBAF improved tumor control alone and in combination with anti-PD-L1. Simultaneous depletion of BAF- and PBAF-specific subunits revealed that BAF is required for the beneficial impact of loss of PBAF on TEX differentiation. Thus, BAF and PBAF regulate epigenetic transitions in CD8 T cell differentiation, with PBAF acting at a later stage in exhaustion as a guardian to limit full TEX differentiation and preserve TEX progenitor populations with implications for cancer immunotherapy.

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Distinct SWI/SNF chromatin remodelling complexes act differentially to maintain stem-like exhausted CD8 T cells [ATAC-seq]

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