PO.IM01.01 · 免疫学
衣康酸通过表观遗传修饰和葡萄糖流重定向促进病毒感染和癌症中记忆性CD8 + T细胞的发育
Itaconate promotes memory CD8 + T cell development by epigenetic modification and glucose flux redirection in viral infection and cancer
作者与单位 Authors & Affiliations
摘要 Abstract
中文摘要
背景：已知协调的代谢改变和表观遗传重塑对T细胞命运决定和功能状态具有关键影响。然而，指导CD8 + T细胞记忆分化的特定外源性代谢信号仍有待充分阐明。
方法：将初始CD45.1⁺ OT-I CD8⁺ T细胞过继转移至感染单核细胞增生李斯特菌的CD45.2小鼠中，以追踪体内分化轨迹。通过单细胞RNA测序分析肿瘤浸润性CD8⁺ T细胞，以描绘T细胞亚簇。机制上，我们使用ATAC-seq分析衣康酸处理下CD8⁺ T细胞的全局染色质可及性，揭示其表观遗传重塑效应。通过表面等离子共振（SPR）和互补生化测定的组合，我们证明衣康酸直接结合赖氨酸去甲基化酶5B（KDM5B）并在功能上拮抗α-酮戊二酸（alpha-KG）。此外，代谢流分析以及NADPH和GSH水平的直接测量证实，衣康酸驱动CD8⁺ T细胞的代谢重编程，以维持氧化还原平衡和记忆分化能力。
结果：我们发现，在免疫应答期间诱导产生的衣康酸是记忆性T细胞（T M）分化的关键促进因子。机制上，衣康酸直接结合KDM5B并作为alpha-KG拮抗剂，竞争性抑制KDM5B依赖的H3K4me3去甲基化。这种抑制导致T M细胞分化所必需基因处的染色质可及性增加。此外，衣康酸将葡萄糖流从糖酵解重定向至PPP，从而确保T M细胞中高水平的NADPH和谷胱甘肽以缓解氧化应激。
结论：我们的结果确定衣康酸是一种关键的免疫代谢调节因子，通过同时调节表观遗传编程和代谢适应性，在病毒感染和癌症中促进持久的免疫记忆。这一机制为增强CAR T细胞的干样表型和持久性提供了一个潜在的治疗靶点。
查看英文原文 English abstract
Background: Coordinated metabolic alterations and epigenetic remodeling are known to critically influence T cell fate decisions and functional states. However, the specific extrinsic metabolic signals that guide CD8 + T cell memory differentiation remain to be fully elucidated.
Methods: Naïve CD45.1⁺ OT-I CD8⁺ T cells were adoptively transferred into Listeria monocytogenes-infected CD45.2 mice to track in vivo differentiation trajectories. Tumor-infiltrating CD8⁺ T cells were analyzed by single-cell RNA sequencing to delineate T cell subclusters. Mechanistically, we profiled global chromatin accessibility of CD8⁺ T cells under itaconate treatment using ATAC-seq, revealing its epigenetic remodeling effects. Through a combination of surface plasmon resonance (SPR) and complementary biochemical assays, we demonstrated that itaconate directly binds to lysine demethylase 5B (KDM5B) and functionally antagonizes alpha-ketoglutarate (alpha-KG). Furthermore, metabolic flux analyses, along with direct measurements of NADPH and GSH levels, confirmed that itaconate drives metabolic reprogramming in CD8⁺ T cells to sustain redox balance and memory differentiation capacity.
Results: We found that itaconate, induced during immune responses, is a critical promoter of memory T cell (T M ) differentiation. Mechanistically, itaconate directly binds to KDM5B and acts as an alpha-KG antagonist, competitively inhibiting KDM5B-dependent demethylation of H3K4me3. This inhibition leads to increased chromatin accessibility at genes essential for T M cell differentiation. Furthermore, itaconate redirects glucose flux from glycolysis to the PPP, thereby ensuring high levels of NADPH and glutathione in TM cells to alleviate oxidative stress.
Conclusions: Our results identify itaconate as a key immunometabolic regulator that promotes durable immune memory in viral infections and cancer by concurrently modulating epigenetic programming and metabolic fitness. This machinery presents a potential therapeutic target to enhance the stem-like phenotype and persistence of CAR T cells.
利益披露 Disclosure
X. Yang, None..
M. Su, None..
J. Wang, None..
Y. Deng, None..
L. Kong, None..
K. Yang, None..
C. Wan, None.