Browse
Submit Data
Databases
API
Help

Dataset Information

36 Views

0 Connections

0 Citations

0 Reanalyses

0 Downloads

Omics score: 0

The Transcription Factor TCF1 Preserves the Effector Function of Exhausted CD8 T Cells During Chronic Viral Infection.

ABSTRACT: The long-term persistence of viral antigens drives virus-specific CD8 T cell exhaustion during chronic viral infection. Yet exhausted, CD8 T cells are still endowed with certain levels of effector function, by which they can keep viral replication in check in chronic infection. However, the regulatory factors involved in regulating the effector function of exhausted CD8 T cell are largely unknown. Using mouse model of chronic LCMV infection, we found that the deletion of transcription factor TCF-1 in LCMV-specific exhausted CD8 T cells led to the profound reduction in cytokine production and degranulation. Conversely, ectopic expression of TCF-1 or using agonist to activate TCF-1 activities promotes the effector function of exhausted CD8 T cells. Mechanistically, TCF-1 fuels the functionalities of exhausted CD8 T cells by promoting the expression of an array of key effector function-associated transcription regulators, including Foxo1, Zeb2, Id3, and Eomes. These results collectively indicate that targeting TCF-1 mediated transcriptional pathway may represent a promising immunotherapy strategy against chronic viral infections by reinvigorating the effector function of exhausted virus-specific CD8 T cells.

SUBMITTER: Wang Y

PROVIDER: S-EPMC6381939 | biostudies-literature |

REPOSITORIES: biostudies-literature

ACCESS DATA

Json Xml

Similar Datasets

Kruppel-like factor 4 regulates the cytolytic effector function of exhausted CD8 T cells

Project description:Exhausted CD8 T cells during chronic inflammatory responses against viral infections and cancer are phenotypically and functionally heterogeneous. In particular, CD8 T cells with cytolytic effector function have been recently identified among the exhausted CD8 T cell subsets. However, the regulation of their differentiation and function remains largely unknown. Here, we report that Krüppel-like factor 4 (KLF4) is a critical regulator of the exhaustion process, promoting the cytolytic effector function of exhausted CD8 T cells. KLF4-expressing CD8 T cells in exhaustion contexts showed the features of transitory effector CD8 T cells. Enforced KLF4 expression increased CD8 T cell differentiation into transitory effector subsets and enhanced their antitumor immunity. We further demonstrated that KLF4 also showed a capacity of reinvigorating exhausted CD8 T cells. Last, high KLF4 expression was positively correlated with a favorable prognosis in human patients with cancer. Our study highlights the potential impacts of KLF4 on CD8 T cell exhaustion and antitumor immune therapy. Description KLF4 regulates the exhaustion process by promoting CD8 T cell differentiation into cytolytic transitory effector subsets.

| S-EPMC9699681 | biostudies-literature

Transcription profiling of mouse naive, effector, memory and exhausted virus-specific CD8 T cells after chronic viral infection

Project description:CD8 T cells normally differentiate from resting naÃ¯ve T cells into function effector and then memory CD8 T cells following acute infections. During chronic viral infections, however, virus-specific CD8 T cells often become exhausted. We used microarrays to examine the gene expression differences between naive, effector, memory and exhausted virus-specific CD8 T cells following lymphocytic choriomeningitis virus infection. Experiment Overall Design: Three or four independent samples were sorted by flow cytometry for each cell type (naive, effector, memory and exhausted) virus-specific CD8 T cells. RNA was extracted and hybridized to Affymetrix microarrays.

2008-06-16 | E-GEOD-9650 | biostudies-arrayexpress

Ectopic Tcf1 expression instills a stem-like program in exhausted CD8<sup>+</sup> T cells to enhance viral and tumor immunity.

Project description:Exhausted CD8+ T (Tex) cells are dysfunctional due to persistent antigen exposure in chronic viral infection and tumor contexts. A stem cell-like Tex (Tex-stem) subset can self-renew and differentiate into terminally exhausted (Tex-term) cells. Here, we show that ectopic Tcf1 expression potently promoted the generation of Tex-stem cells in both a chronic viral infection and preclinical tumor models. Tcf1 overexpression diminished coinhibitory receptor expression and enhanced polycytokine-producing capacity while retaining a heightened responses to checkpoint blockade, leading to enhanced viral and tumor control. Mechanistically, ectopically expressed Tcf1 exploited existing and novel chromatin accessible sites as transcriptional enhancers or repressors and modulated the transcriptome by enforcing pre-existing expression patterns in Tex-stem cells, such as enhanced suppression of Blimp1 and Bim and acquisition of new downstream genes, including Mx1, Tox2, and Runx3. These findings reveal a pronounced impact of ectopic Tcf1 expression on Tex functional restoration and highlight the therapeutic potential of harnessing Tcf1-enforced transcriptional programs.

| S-EPMC8093427 | biostudies-literature

Chronic viral infection of naive, effector, memory and exhausted virus-specific CD8 T cells

Project description:CD8 T cells normally differentiate from resting naïve T cells into function effector and then memory CD8 T cells following acute infections. During chronic viral infections, however, virus-specific CD8 T cells often become exhausted. We used microarrays to examine the gene expression differences between naive, effector, memory and exhausted virus-specific CD8 T cells following lymphocytic choriomeningitis virus infection. Keywords: infection response

2007-11-27 | GSE9650 | GEO

Antigen-specific CD4 T-cell help rescues exhausted CD8 T cells during chronic viral infection.

Project description:CD4 T cells play a critical role in regulating CD8 T-cell responses during chronic viral infection. Several studies in animal models and humans have shown that the absence of CD4 T-cell help results in severe dysfunction of virus-specific CD8 T cells. However, whether function can be restored in already exhausted CD8 T cells by providing CD4 T-cell help at a later time remains unexplored. In this study, we used a mouse model of chronic lymphocytic choriomeningitis virus (LCMV) infection to address this question. Adoptive transfer of LCMV-specific CD4 T cells into chronically infected mice restored proliferation and cytokine production by exhausted virus-specific CD8 T cells and reduced viral burden. Although the transferred CD4 T cells were able to enhance function in exhausted CD8 T cells, these CD4 T cells expressed high levels of the programmed cell death (PD)-1 inhibitory receptor. Blockade of the PD-1 pathway increased the ability of transferred LCMV-specific CD4 T cells to produce effector cytokines, improved rescue of exhausted CD8 T cells, and resulted in a striking reduction in viral load. These results suggest that CD4 T-cell immunotherapy alone or in conjunction with blockade of inhibitory receptors may be a promising approach for treating CD8 T-cell dysfunction in chronic infections and cancer.

| S-EPMC3248546 | biostudies-literature

Krüppel-like factor 4 regulates the cytolytic effector function of exhausted CD8 T-cells

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

2022-10-24 | GSE212806 | GEO

Transcription Factor Bcl11b Controls Effector and Memory CD8 T cell Fate Decision and Function during Poxvirus Infection.

Project description:CD8+ T cells play an important role in host resistance to many viral infections, but the underlying transcriptional mechanisms governing their differentiation and functionality remain poorly defined. By using a highly virulent systemic and respiratory poxvirus infection in mice, we show that the transcription factor Bcl11b provides a dual trigger that sustains the clonal expansion of virus-specific effector CD8+ T cells, while simultaneously suppressing the expression of surface markers associated with short-lived effector cell (SLEC) differentiation. Additionally, we demonstrate that Bcl11b supports the acquisition of memory precursor effector cell (MPEC) phenotype and, thus, its absence causes near complete loss of lymphoid and lung-resident memory cells. Interestingly, despite having normal levels of T-bet and Eomesodermin, Bcl11b-deficient CD8+ T cells failed to execute effector differentiation needed for anti-viral cytokine production and degranulation, suggesting a non-redundant role of Bcl11b in regulation of this program. Thus, Bcl11b is a critical player in fate decision of SLECs and MPECs, as well as effector function and memory formation.

| S-EPMC5061747 | biostudies-literature

Krüppel-like factor 4 regulates the cytolytic effector function of exhausted CD8 T-cells [ATAC-Seq]

Project description:Since exhausted CD8 T-cells are known to have a strong epigenetic imprint, which is a major obstacle for reinvigoration, we investigated whether the induced Klf4 expression could change the epigenetic status of the exhausted CD8 T-cells. For this, we performed ATAC-sequencing and compared chromatin landscapes between naïve, in vitro generated effector, exhausted (GFP-induced), and reinvigorated (KLF4-induced) CD8 T-cells.

2022-10-24 | GSE212805 | GEO

Krüppel-like factor 4 regulates the cytolytic effector function of exhausted CD8 T-cells [RNA-Seq]

Project description:To identify the role of KLF4 on exhausted CD8 T-cells, we retrovirally transduced Klf4 into OT-I CD8 T-cells on day1 of in vitro exhaustion model and repeatedly treated OVA peptide to induce exhaustion. Then we analyzed the gene expression profiles of these transduced cells by RNA-sequencing.

2022-10-24 | GSE212804 | GEO

Krüppel-like factor 4 regulates the cytolytic effector function of exhausted CD8 T-cells [SMART-Seq]

Project description:To identify the role of KLF4 on exhausted CD8 T-cells in vivo, we adoptively transferred PmelI CD8 T-cells transduced with MigRI/Klf4 into MC38-gp100 tumor-bearing Rag2 KO mice on day7. We then isolated tumor-infiltrating PmelI CD8 T-cells on day15 and their gene expression profiles were analyzed by SMART-seq. Also, to investigate the effect of KLF4 deficiency, we isolated PD1+ CD8+ TILs from MC38 tumor-bearing control and Klf4 cKO mice on day14, and SMART-seq was performed.

2022-10-24 | GSE212803 | GEO

OmicsDI is part of the ELIXIR infrastructure

OmicsDI is an Elixir interoperability service. Learn more ›

Tweets

OmicsDI Databases

PRIDE
PeptideAtlas
MassIVE
JPOST Repository
Physiome Model Repository

EGA
EVA
ENA
LINCS
PAXDB
Cell Collective

MetaboLights
Metabolomics Workbench
MetabolomeExpress
GNPS
BioModels
FAIRDOMHub

ArrayExpress
dbGaP
ExpressionAtlas
GEO
NODE

Information

Databases
Help
API
Contact us
Code on GitHub
Terms of use
Submit Data