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Neonatal CD8+ T cells resist terminal exhaustion during chronic infection

ABSTRACT: Neonatal CD8+ T cells resist terminal exhaustion during chronic infection

PROVIDER: PRJNA980733 | ENA |

REPOSITORIES: ENA

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			Action	DRS
	SRR24839052_1.fastq.gz	Fastqsanger.gz
	SRR24839052_2.fastq.gz	Fastqsanger.gz
	SRR24839053_1.fastq.gz	Fastqsanger.gz
	SRR24839053_2.fastq.gz	Fastqsanger.gz
	SRR24839054_1.fastq.gz	Fastqsanger.gz

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Neonatal CD8+ T cells resist terminal exhaustion during chronic infection [RNAseq_day30]

Project description:Neonatal CD8+ T cells resist terminal exhaustion during chronic infection [RNAseq_day30]

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Neonatal CD8+ T cells resist terminal exhaustion during chronic infection [RNAseq_day8]

Project description:Neonatal CD8+ T cells resist terminal exhaustion during chronic infection [RNAseq_day8]

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Neonatal CD8+ T cells resist terminal exhaustion during chronic infection [RNAseq_day30]

Project description:Chronic viral infections represent a major public health problem. Although it is well understood that neonates and adults respond differently to chronic viral infections (HIV, HCV), the underlying mechanisms remain poorly understood. In this study, we transferred neonatal and adult CD8+ T cells into a mouse model of chronic infection (LCMV clone 13) and dissected out the key cell-intrinsic differences that alter their ability to protect the host. Interestingly, we found that neonatal CD8+ T cells preferentially become effector cells early in chronic infection when compared to adult CD8+ T cells, and resist commitment to the exhausted differentiation trajectory. Further, neonatal CD8+ T cells are preferentially maintained as stem-like exhausted progenitors rather than terminally exhausted cells during the chronic phase of infection. The altered differentiation trajectories of neonatal and adult CD8+ T cells is functionally significant, for the neonatal cells protect from viral replication. Together, our work demonstrates how cell-intrinsic differences between neonatal and adult CD8+ T cells influences key cell fate decisions during chronic infection.

2024-03-07 | GSE234303 | GEO

Neonatal CD8+ T cells resist terminal exhaustion during chronic infection [RNAseq_day8]

Project description:Chronic viral infections represent a major public health problem. Although it is well understood that neonates and adults respond differently to chronic viral infections (HIV, HCV), the underlying mechanisms remain poorly understood. In this study, we transferred neonatal and adult CD8+ T cells into a mouse model of chronic infection (LCMV clone 13) and dissected out the key cell-intrinsic differences that alter their ability to protect the host. Interestingly, we found that neonatal CD8+ T cells preferentially become effector cells early in chronic infection when compared to adult CD8+ T cells, and resist commitment to the exhausted differentiation trajectory. Further, neonatal CD8+ T cells are preferentially maintained as stem-like exhausted progenitors rather than terminally exhausted cells during the chronic phase of infection. The altered differentiation trajectories of neonatal and adult CD8+ T cells is functionally significant, for the neonatal cells protect from viral replication at the cost of early-onset immunopathology. Together, our work demonstrates how cell-intrinsic differences between neonatal and adult CD8+ T cells influences key cell fate decisions during chronic infection.

2024-03-07 | GSE234302 | GEO

Neonatal CD8+ T Cells Resist Exhaustion during Chronic Infection.

Project description:Chronic viral infections, such as HIV and hepatitis C virus, represent a major public health problem. Although it is well understood that neonates and adults respond differently to chronic viral infections, the underlying mechanisms remain unknown. In this study, we transferred neonatal and adult CD8+ T cells into a mouse model of chronic infection (lymphocytic choriomeningitis virus clone 13) and dissected out the key cell-intrinsic differences that alter their ability to protect the host. Interestingly, we found that neonatal CD8+ T cells preferentially became effector cells early in chronic infection compared with adult CD8+ T cells and expressed higher levels of genes associated with cell migration and effector cell differentiation. During the chronic phase of infection, the neonatal cells retained more immune functionality and expressed lower levels of surface markers and genes related to exhaustion. Because the neonatal cells protect from viral replication early in chronic infection, the altered differentiation trajectories of neonatal and adult CD8+ T cells is functionally significant. Together, our work demonstrates how cell-intrinsic differences between neonatal and adult CD8+ T cells influence key cell fate decisions during chronic infection.

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Neonatal CD8+ T cells resist terminal exhaustion during chronic infection

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

2024-03-06 | GSE234309 | GEO

MEK-dependent bioenergetic demand drives terminal CD8+ T cell exhaustion

Project description:Loss of mitochondrial function contributes to CD8+ T cell dysfunction during persistent antigen encounter. How chronic antigen leads to this metabolic dysfunction remains unclear. Here, we show that TCR-dependent mitochondrial NADH accumulation drives production of ROS, ultimately leading to mitochondrial dysfunction. Among TCR-dependent proximal signaling components, MEKi uniquely reduced nutrient uptake and mitochondrial NADH accumulation while increasing proliferation. As a result, MEKi during chronic TCR stimulation reduced terminal T cell exhaustion. Mechanistically, we found that chronic MEK activation in T cells drove ATP demand by increasing global protein synthesis rates in vitro and in vivo. MEKi reversed chronic TCR stimulation-driven increases in RNA polymerase II CTD phosphorylation, reducing transcription rates at effector- and terminal-exhaustion associated genes while maintaining transcription of memory-associated genes. These findings establish MEK-dependent metabolic demand as a driver of T cell exhaustion and elucidate the role of MEKi in enhancing immunotherapy efficacy.

2025-04-02 | GSE293649 | GEO

MEK-dependent bioenergetic demand drives terminal CD8+ T cell exhaustion

Project description:MEK-dependent bioenergetic demand drives terminal CD8+ T cell exhaustion

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Chronic Type I interferons signaling promotes lipid peroxidation-driven terminal CD8+T cell exhaustion and curtails anti-PD-1 treatment efficacy

Project description:Identifying signals that govern the differentiation of tumor-infiltrating CD8 + T cells (CD8 + TILs) towards exhaustion can improve current therapeutic approaches for cancer. Here, we show that type I interferons (IFN-Is) act as environmental cues enhancing terminal CD8 + T cell exhaustion in tumors. We found enrichment of IFNIs-stimulated genes (ISGs) within exhausted CD8 + T cells (Tex cells) in patients across various cancer types, with heightened ISG levels correlating with poor response to immune checkpoint blockade (ICB) therapy. In preclinical models, CD8 + TILs devoid of IFN-Is signaling developed less exhaustion features, provided better tumor control and showed greater response to ICB-mediated rejuvenation. Mechanistically, chronic IFN-Is stimulation perturbed lipid metabolism and redox balance in Tex cells, leading to aberrant lipid accumulation and elevated oxidative stress. Collectively, these defects promoted lipid peroxidation, which potentiated metabolic and functional exhaustion of Tex cells. Thus, cell intrinsic IFN-Is signaling regulates the extent of CD8+ TIL exhaustion, and has important implications for immunotherapy.

2022-11-16 | GSE212699 | GEO

Chronic Type I interferons signaling promotes lipid peroxidation-driven terminal CD8+T cell exhaustion and curtails anti-PD-1 treatment efficacy [ATAC-Seq]

2022-11-16 | GSE212698 | GEO