Browse
Submit Data
Databases
API
Help

Dataset Information

21 Views

0 Connections

0 Citations

0 Reanalyses

0 Downloads

Omics score: 0

Developmental Relationships of Four Exhausted CD8⁺ T Cell Subsets Reveals Underlying Transcriptional and Epigenetic Landscape Control Mechanisms.

ABSTRACT: CD8⁺ T cell exhaustion is a major barrier to current anti-cancer immunotherapies. Despite this, the developmental biology of exhausted CD8⁺ T cells (Tex) remains poorly defined, restraining improvement of strategies aimed at "re-invigorating" Tex cells. Here, we defined a four-cell-stage developmental framework for Tex cells. Two TCF1⁺ progenitor subsets were identified, one tissue restricted and quiescent and one more blood accessible, that gradually lost TCF1 as it divided and converted to a third intermediate Tex subset. This intermediate subset re-engaged some effector biology and increased upon PD-L1 blockade but ultimately converted into a fourth, terminally exhausted subset. By using transcriptional and epigenetic analyses, we identified the control mechanisms underlying subset transitions and defined a key interplay between TCF1, T-bet, and Tox in the process. These data reveal a four-stage developmental hierarchy for Tex cells and define the molecular, transcriptional, and epigenetic mechanisms that could provide opportunities to improve cancer immunotherapy.

SUBMITTER: Beltra JC

PROVIDER: S-EPMC8360766 | biostudies-literature |

REPOSITORIES: biostudies-literature

ACCESS DATA

Json Xml

Similar Datasets

Epigenetic landscape of four exhausted CD8 T cell subsets

Project description:Open chromatin accessibility analysis of four defiined CD8 Tcell subsets to understand the mechanism of exhaustion hierarchy

2020-05-11 | GSE149877 | GEO

Landscape of four exhausted CD8 T cell subsets

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

2020-05-11 | GSE149879 | GEO

Transcriptional landscape of four exhausted CD8 T cell subsets

Project description:Transcriptional study of four defiined CD8 Tcell subset to understand the mechanism of exhaustion hierarchy

2020-05-11 | GSE149876 | GEO

Epigenetic landscape of four exhausted CD8 T cell subsets

Project description:Epigenetic landscape of four exhausted CD8 T cell subsets

| PRJNA630423 | ENA

Landscape of four exhausted CD8 T cell subsets

Project description:Landscape of four exhausted CD8 T cell subsets

| PRJNA630420 | ENA

Subsets of exhausted CD8+ T cells differentially mediate tumor control and respond to checkpoint blockade.

Project description:T cell dysfunction is a hallmark of many cancers, but the basis for T cell dysfunction and the mechanisms by which antibody blockade of the inhibitory receptor PD-1 (anti-PD-1) reinvigorates T cells are not fully understood. Here we show that such therapy acts on a specific subpopulation of exhausted CD8+ tumor-infiltrating lymphocytes (TILs). Dysfunctional CD8+ TILs possess canonical epigenetic and transcriptional features of exhaustion that mirror those seen in chronic viral infection. Exhausted CD8+ TILs include a subpopulation of 'progenitor exhausted' cells that retain polyfunctionality, persist long term and differentiate into 'terminally exhausted' TILs. Consequently, progenitor exhausted CD8+ TILs are better able to control tumor growth than are terminally exhausted T cells. Progenitor exhausted TILs can respond to anti-PD-1 therapy, but terminally exhausted TILs cannot. Patients with melanoma who have a higher percentage of progenitor exhausted cells experience a longer duration of response to checkpoint-blockade therapy. Thus, approaches to expand the population of progenitor exhausted CD8+ T cells might be an important component of improving the response to checkpoint blockade.

| S-EPMC6673650 | biostudies-literature

Transcriptional landscape of four exhausted CD8 T cell subsets

Project description:Transcriptional landscape of four exhausted CD8 T cell subsets

| PRJNA630424 | ENA

Transcriptional landscape of three exhausted CD8 T cell subsets

Project description:Transcriptional analysis of exhausted CD8 Tcell subsets after eliminating chronic antigen stimulation at the single cell level

2021-02-01 | GSE150369 | GEO

Mitochondrial superoxide disrupts the metabolic and epigenetic landscape of CD4+ and CD8+ T-lymphocytes.

Project description:While the role of mitochondrial metabolism in controlling T-lymphocyte activation and function is becoming more clear, the specifics of how mitochondrial redox signaling contributes to T-lymphocyte regulation remains elusive. Here, we examined the global effects of elevated mitochondrial superoxide (O2-) on T-lymphocyte activation using a novel model of inducible manganese superoxide dismutase (MnSOD) knock-out. Loss of MnSOD led to specific increases in mitochondrial O2- with no evident changes in hydrogen peroxide (H2O2), peroxynitrite (ONOO-), or copper/zinc superoxide dismutase (CuZnSOD) levels. Unexpectedly, both mitochondrial and glycolytic metabolism showed significant reductions in baseline, maximal capacities, and ATP production with increased mitochondrial O2- levels. MnSOD knock-out T-lymphocytes demonstrated aberrant activation including widespread dysregulation in cytokine production and increased cellular apoptosis. Interestingly, an elevated proliferative signature defined by significant upregulation of cell cycle regulatory genes was also evident in MnSOD knock-out T-lymphocytes, but these cells did not show accelerated proliferative rates. Global disruption in T-lymphocyte DNA methylation and hydroxymethylation was also observed with increased mitochondrial O2-, which was correlated to alterations in intracellular metabolite pools linked to the methionine cycle. Together, these results demonstrate a mitochondrial redox and metabolic couple that when disrupted may alter cellular processes necessary for proper T-lymphocyte activation.

| S-EPMC6859572 | biostudies-literature

Lineage relationship of CD8(+) T cell subsets is revealed by progressive changes in the epigenetic landscape.

Project description:To better elucidate epigenetic mechanisms that correlate with the dynamic gene expression program observed upon T-cell differentiation, we investigated the genomic landscape of histone modifications in naive and memory CD8(+) T cells. Using a ChIP-Seq approach coupled with global gene expression profiling, we generated genome-wide histone H3 lysine 4 (H3K4me3) and H3 lysine 27 (H3K27me3) trimethylation maps in naive, T memory stem cells, central memory cells, and effector memory cells in order to gain insight into how histone architecture is remodeled during T cell differentiation. We show that H3K4me3 histone modifications are associated with activation of genes, while H3K27me3 is negatively correlated with gene expression at canonical loci and enhancers associated with T-cell metabolism, effector function, and memory. Our results also reveal histone modifications and gene expression signatures that distinguish the recently identified T memory stem cells from other CD8(+) T-cell subsets. Taken together, our results suggest that CD8(+) lymphocytes undergo chromatin remodeling in a progressive fashion. These findings have major implications for our understanding of peripheral T-cell ontogeny and the formation of immunological memory.

| S-EPMC4947817 | biostudies-literature