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Bcl11b dose-dependently regulates positive selection of CD8 T cells to the virtual memory fate [ATAC-seq]

ABSTRACT: Bcl11b is indispensable for establishing and maintaining T cell identity; however, its expression levels differ among T cell lineages and activation states. Three different genetic models of Bcl11b gene dosage reduction revealed that a <2-fold reduction of Bcl11b protein level redirects CD8 T cell differentiation preferentially to virtual memory fate, at the expense of the naïve compartment. This expanded TVM compartment appeared functionally normal, while remaining naïve CD8 T cells were more sensitive to stimulation. Timed conditional knockouts and adoptive transfers narrowed the developmental window involved and showed that reduced Bcl11b levels determine diversion to virtual memory fate during intrathymic positive selection. Whereas select target genes were affected, single-cell RNA-seq found that Bcl11b dose primarily controls the flux of thymic precursors to different mature fates. In addition to a modest impact on mitochondrial potential, Bcl11b dose appears to restrict the capacity of cycling CD8SP thymocytes specifically to express a TVM transcriptional program.

ORGANISM(S): Mus musculus

PROVIDER: GSE333222 | GEO | 2026/09/15

REPOSITORIES: GEO

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Bcl11b dose-dependently regulates positive selection of CD8 T cells to the virtual memory fate

Project description:Bcl11b is indispensable for establishing and maintaining T cell identity; however, its expression levels differ among T cell lineages and activation states. Three different genetic models of Bcl11b gene dosage reduction revealed that a <2-fold reduction of Bcl11b protein level redirects CD8 T cell differentiation preferentially to virtual memory fate, at the expense of the naïve compartment. This expanded TVM compartment appeared functionally normal, while remaining naïve CD8 T cells were more sensitive to stimulation. Timed conditional knockouts and adoptive transfers narrowed the developmental window involved and showed that reduced Bcl11b levels determine diversion to virtual memory fate during intrathymic positive selection. Whereas select target genes were affected, single-cell RNA-seq found that Bcl11b dose primarily controls the flux of thymic precursors to different mature fates. In addition to a modest impact on mitochondrial potential, Bcl11b dose appears to restrict the capacity of cycling CD8SP thymocytes specifically to express a TVM transcriptional program.

2026-09-15 | GSE333224 | GEO

Bcl11b dose-dependently regulates positive selection of CD8 T cells to the virtual memory fate [RNA-seq]

Project description:Bcl11b is indispensable for establishing and maintaining T cell identity; however, its expression levels differ among T cell lineages and activation states. Three different genetic models of Bcl11b gene dosage reduction revealed that a <2-fold reduction of Bcl11b protein level redirects CD8 T cell differentiation preferentially to virtual memory fate, at the expense of the naive compartment. This expanded TVM compartment appeared functionally normal, while remaining naive CD8 T cells were more sensitive to stimulation. Timed conditional knockouts and adoptive transfers narrowed the developmental window involved and showed that reduced Bcl11b levels determine diversion to virtual memory fate during intrathymic positive selection. Whereas select target genes were affected, single-cell RNA-seq found that Bcl11b dose primarily controls the flux of thymic precursors to different mature fates. In addition to a modest impact on mitochondrial potential, Bcl11b dose appears to restrict the capacity of cycling CD8SP thymocytes specifically to express a TVM transcriptional program.

2026-09-15 | GSE333223 | GEO

Comparison of young and aged mouse CD8 TN, TVM and TMEM cells directly ex vivo and after polyclonal stimulation

Project description:The overall study (Quinn et al. Cell Reports, 2018) aimed to understand why CD8 virtual memory T (TVM) cells become markedly less proliferative in response to TCR-driven signals with increasing age, whereas CD8 true naive (TN) cells maintain their proliferative capacity. Age-associated decreases in primary CD8+ T cell responses occur, in part, due to direct effects on naïve CD8++ T cells to reduce intrinsic functionality, but the precise nature of this defect remains undefined. Ageing also causes accumulation of antigen-naïve but semi-differentiated “virtual memory” (TVM) cells but their contribution to age-related functional decline is unclear. Here, we show that TVM cells are poorly proliferative in aged mice and humans, despite being highly proliferative in young individuals, while conventional naïve T cells (TN cells) retain proliferative capacity in both aged mice and humans. Adoptive transfer experiments in mice illustrated that naïve CD8 T cells can acquire a proliferative defect imposed by the aged environment but age-related proliferative dysfunction could not be rescued by a young environment. Molecular analyses demonstrate that aged TVM cells exhibit a profile consistent with senescence, marking the first description of senescence in an antigenically naïve T cell population.

2018-06-19 | GSE112304 | GEO

Bcl11b dose-dependently regulates positive selection of CD8 T cells to the virtual memory fate

Project description:Bcl11b dose-dependently regulates positive selection of CD8 T cells to the virtual memory fate

| PRJNA1470512 | ENA

Bcl11b dose-dependently regulates positive selection of CD8 T cells to the virtual memory fate [ATAC-seq]

Project description:Bcl11b dose-dependently regulates positive selection of CD8 T cells to the virtual memory fate [ATAC-seq]

| PRJNA1470513 | ENA

Bcl11b dose-dependently regulates positive selection of CD8 T cells to the virtual memory fate [RNA-seq]

Project description:Bcl11b dose-dependently regulates positive selection of CD8 T cells to the virtual memory fate [RNA-seq]

| PRJNA1470518 | ENA

RNA-seq data of virtual memory T cells In vitro induced from WT and DUSP2-/- CD8+ T cells

Project description:Virtual memory CD8+ T (TVM) cells are a distinct subset of antigen-inexperienced cells with rapid effector potential, but their regulatory checkpoints remain elusive. Here, using bulk RNA sequencing, we found that DUSP2 intrinsically limits the differentiation of highly activated TVM cells, thereby constraining antiviral immunity.

2026-04-29 | GSE329037 | GEO

Virtual memory T-cells orchestrate extra-lymphoid responses conducive to resident memory

Project description:A primary immune response is typically initiated in secondary lymphoid organs. Virtual memory CD8+ T (TVM) cells are antigen-inexperienced T cells of a central-memory phenotype, acquired through self antigen-driven homeostatic proliferation. Unexpectedly, here we find that, TVM cells are composed of CCR2+ and CCR2- subsets that differentially elaborate a spectrum of effector- and memory-poised functions directly in the tissue. During a primary flu infection, TVM cells rapidly infiltrate the lung in the first day and execute early viral control. TVM cells that recognize viral antigen are retained in the tissue, clonally expand independent of secondary lymphoid organs, and preferentially give rise to tissue-resident memory cells. By orchestrating an extra-lymphoid primary response, heterogenous TVM cells bridge innate reaction and adaptive memory directly in the infected tissue.

2021-06-15 | GSE148364 | GEO

DNA:RNA ImmunoPrecipitation (DRIP) sequencing data of virtual memory T cells In vitro induced from WT and Dusp2-/- CD8+ T cells

Project description:Virtual memory CD8+ T (TVM) cells are a distinct subset of antigen-inexperienced cells with rapid effector potential, but their regulatory checkpoints remain elusive. Here, using DRIP sequencing, we found that loss of DUSP2 promotes aberrant R-loop accumulation, leading to enhanced chromatin accessibility and subsequent TVM cell differentiation.

2026-04-29 | GSE329041 | GEO

Single-cell transcriptomic analysis of CD8+ T cells from peripheral blood of WT and Dusp2-/- mice

Project description:Virtual memory CD8+ T (TVM) cells are a distinct subset of antigen-inexperienced cells with rapid effector potential, but their regulatory checkpoints remain elusive. Here, using single-cell transcriptomic profiling, we found that depletion of DUSP2 drives the expansion of CD44super-high TVM subset with heightened effector signatures.

2026-04-29 | GSE329034 | GEO

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