T细胞,SCI z-bio 2024-12-19 1706

　　In cancer and chronic viral infections, exhausted T cells (TEX) undergo a series of metabolic and epigenetic remodeling, weakening their immune protective abilities. However, it has not been clear how nutritional metabolism specifically affects epigenetic modifications that control TEX differentiation.

　　On December 13, 2024, Ma Shixin, a countrymen scholar from the Susan M. Kaech team of the Salk Institute of Biology, as the first author, published a research paper entitled "Nutrient driven histone code decisions evolved CD8+T cell factors" on Science, revealing the key influence of nutrition metabolism on the fate of depleted CD8+T cells (TEX) and the underlying mechanism.

　　Research has shown that in cancer and chronic viral infections, TEX cells shift from acetate metabolism to citrate metabolism pathway by downregulating acetyl CoA synthase 2 (ACSS2) while maintaining ATP citrate lyase (ACLY) activity. This metabolic conversion increases citrate dependent histone acetylation, particularly on TEX characteristic genes, while reducing acetate dependent histone acetylation on effector and memory T cell genes. Overexpression of ACSS2 or inhibition of ACLY in the nucleus can prevent TEX differentiation and enhance tumor specific T cell response.

　　This study reveals a nutrition driven histone code that determines the fate of CD8+T cells, providing important theoretical basis and practical guidance for novel T cell therapies based on metabolism and epigenetics.

　　In addition to transcription and epigenetic reprogramming, metabolic reprogramming is also an important feature of TEX cells. Effect T cells (TEFF) support their growth, proliferation, and effector function through efficient glucose and amino acid metabolism, while TEX cells undergo a gradual shift in their nutritional metabolism pattern, characterized by decreased mitochondrial function, increased dependence on glycolysis, and increased uptake of oxidized lipids, which impair their functional capacity.

　　Metabolic intermediates, such as acetyl CoA, act as substrates for histone acetylation and participate in modifying the cell's epigenome. In mammalian cells, acetyl CoA is mainly synthesized from acetate and citrate by acetyl CoA synthase 2 (ACSS2) and ATP citrate lyase (ACLY). However, it is currently unclear whether the acetyl CoA generated by these enzymes (such as ACSS2 and ACLY) plays an important role in determining the unique epigenetic features and differentiation patterns of CD8+T cells in tumors and chronic infections.

　　To explore the role of nutritional metabolism in epigenetic modifications during CD8+T cell differentiation. The researchers first validated the differential expression of ACSS2 and ACLY in TEFF and TEX cells through transcriptome analysis and Western blot. The results showed that TEX cells downregulated ACSS2 expression while maintaining ACLY expression during tumor and chronic infection. Does it mean that these two modes have opposite effects?

　　Subsequently, the research team used gene knockout methods to investigate the roles of ACSS2 and ACLY in the formation of TEX cells during tumorigenesis and chronic LCMV infection. It was found that in the case of T cell failure, the absence of Acss2 weakens the activity of CD8+T cells, while the absence of Acly enhances their function.

　　This raises a new scientific question: Does the acetyl CoA generated by ACLY and ACSS2 determine the formation of TEX?

　　The research team tracked the pathway of acetic acid and glucose metabolism to produce acetyl CoA through isotope tracing experiments, and combined histone acetylation analysis and CUT&Tag sequencing technology to explore in depth how ACSS2 and ACLY regulate the histone acetylation levels of TEXProg and TEXterm related genes through p300 and KAT2A histone acetyltransferases, respectively. Research has found that ACSS2 mainly promotes histone acetylation of functional effector T cell (TEFF) genes through p300 under acute stimulation, while ACLY enhances acetylation of exhausted T cell (TEXterm) genes through KAT2A under chronic stimulation.

　　Further research utilized ACSS2 overexpression vectors labeled with nuclear localization signals and ACLY inhibitor BMS-303141 to evaluate the potential of these interventions in restoring T cell function and enhancing anti-tumor immune response. The results showed that overexpression of ACSS2 or inhibition of ACLY not only prevented the differentiation of TEX cells, but also significantly enhanced the anti-tumor activity of T cells.

　　In summary, this study reveals for the first time that although the intermediate products of nutritional metabolism are the same, different types of nutrients play a crucial role in regulating cell fate and function, providing a new perspective for studying cellular nutritional metabolism. By delving into the roles of ACSS2 and ACLY in T cell exhaustion (TEX), this work not only deepens our understanding of the TEX mechanism, but also provides important practical guidance for improving existing immunotherapy strategies. Its research results are expected to promote the development of personalized medicine, especially in the treatment of cancer and chronic infections, demonstrating broad application prospects.