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Nutrient-driven histone code determines exhausted CD8+ T cell fates
Shixin Ma. et al.
Science. 2024
T cell exhaustion is characterized by the impairment of function of antigen-specific T cells, which severely limits immune responses in contexts like cancer and chronic infections. How metabolic signals might influence epigenetic modifications in T cell differentiation is currently unknown, which are crucial for regulating exhausted T cells (TEX) differentiation. The study employed a combination of transcriptomic, metabolomic, and epigenomic profiling to investigate the effects of nutrient signals on T cell function. The authors revealed that metabolic pathways linked to nutrient availability, such as those involving glucose and fatty acid metabolism, could modulate histone modifications. Specifically, they found that metabolic switch from acetate to citrate metabolism increased citrate-dependent histone acetylation, mediated by histone acetyltransferase KAT2A-ACLY interactions. Such metabolic switch was accomplished by downregulating acetyl-CoA synthetase 2 (ACSS2) while maintaining ATP-citrate lyase (ACLY) activity. These histone modifications were shown to directly affect the expression of genes associated with T cell exhaustion, suggesting that metabolic signals play a critical role in determining whether T cells undergo exhaustion or remain functional. In conclusion, manipulating metabolic pathways and the associated epigenetic modifications could provide a novel therapeutic strategy to reverse T cell exhaustion and improve immune responses in chronic infections and cancer.
DOI: 10.1126/science.adj3020
02
Han Chen. et al.
Cell. 2024
The potential impact of dietary interventions particularly intermittent fasting (IF) on various physiological processes is yet to be illustrated. In the presenting paper, the authors employed high-throughput transcriptomic analysis and conditional knockout mouse model to investigate the effects of IF on hair follicle biology. The results indicated that modern intermittent fasting regimens inhibited hair follicle regeneration by selectively inducing apoptosis in activated hair follicle stem cells (HFSCs), but not epidermal stem cells (EpiSCs). Specifically, IF led to an activation of the crosstalk between adrenal glands and dermal adipocytes in the skin. Such interaction triggered the rapid release of free fatty acids into the niche, which in turn disrupted the normal metabolism of HFSCs and elevated their cellular reactive oxygen species levels, causing oxidative damage and apoptosis. They further conducted a randomized clinical trial to confirm that IF could inhibit human hair growth. In conclusion, the study highlighted that intermittent fasting, rather than promoting hair regeneration, may actually suppress it through harming follicle stem cells. These findings illustrate the principles and mechanisms through which intermittent fasting profoundly influences somatic stem cells and tissue biology and delineate a comprehensive strategy for studying such impacts.
DOI: 10.1016/j.cell.2024.11.004
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