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

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

PROVIDER: PRJNA1245427 | ENA |

REPOSITORIES: ENA

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			Action	DRS
	SRR32960446_1.fastq.gz	Fastqsanger.gz
	SRR32960446_2.fastq.gz	Fastqsanger.gz
	SRR32960447_1.fastq.gz	Fastqsanger.gz
	SRR32960447_2.fastq.gz	Fastqsanger.gz
	SRR32960448_1.fastq.gz	Fastqsanger.gz

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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.

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Reversible mitochondrial dysfunction drives terminal T-cell exhaustion

Project description:The failure of T-cells to control tumor growth has been associated with several functional defects that collectively lead to T-cell “exhaustion.” This phenotype results from chronic antigen stimulation within the tumor microenvironment, but how repetitive antigenic stimulation leads to T-cell exhaustion remains poorly defined. Here we show that persistent antigen stimulation induces mitochondrial oxidative stress that reduces tricarboxylic acid (TCA) cycle activity. The resultant bioenergetic compromise impairs nucleotide triphosphate synthesis, induces endoplasmic reticulum (ER) stress, and activates an exhaustion-associated gene expression program. Reversal of oxidative stress with N-acetylcysteine effectively restores T-cell proliferation, effector function, and memory-associated gene expression and enhances anti-tumor T-cell efficacy in vivo. These data reveal that induction of mitochondrial oxidative stress is a critical component of terminal T-cell dysfunction. Furthermore, treatments that restore mitochondrial redox are sufficient to prevent T-cell exhaustion and enhance anti-tumor immunity.

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Reversible mitochondrial dysfunction drives terminal T-cell exhaustion

Project description:Reversible mitochondrial dysfunction drives terminal T-cell exhaustion

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Neonatal CD8+ T cells resist terminal exhaustion during chronic infection

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

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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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A bioenergetic shift is required for spermatogonial differentiation

Project description:A bioenergetic balance between glycolysis and mitochondrial respiration is particularly important for stem cell fate specification. It however remains to be determined whether undifferentiated spermatogonia switch their preference of bioenergy production during differentiation. In this study, we found that ATP generation in spermatogonia was gradually increased upon retinoic acid-induced differentiation. To accommodate this elevated energy demand, retinoic acid signaling concomitantly switched ATP production in spermatogonia from glycolysis to mitochondrial respiration, accompanied by increased levels of reactive oxygen species. In addition, inhibition of glucose conversion to glucose-6-phosphate or pentose phosphate pathway blocked the formation of c-Kit+ differentiating germ cells, suggesting that metabolites produced from glycolysis are required for spermatogonial differentiation. We further demonstrated that the expression levels of several metabolic regulators and enzymes were significantly altered upon retinoic acid-induced differentiation by both RNA-seq analyses and quantitative proteomics. Taken together, our data unveil a critically regulated bioenergetic balance between glycolysis and mitochondrial respiration which is required for spermatogonial proliferation and differentiation.

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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.

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