During an immune response, CD8⁺ T lymphocytes can undergo asymmetric division, giving rise to daughter cells that exhibit distinct tendencies to adopt terminal effector and memory cell fates. Here we show that “pre-effector” and “pre-memory” cells resulting from the first CD8⁺ T cell division in vivo exhibited low and high rates of endogenous proteasome activity, respectively. Pharmacologic reduction of proteasome activity in CD8⁺ T cells early during differentiation resulted in acquisition of terminal effector cell characteristics, whereas enhancement of proteasome activity conferred attributes of memory lymphocytes. Transcriptomic and proteomic analyses revealed that modulating proteasome activity in CD8⁺ T cells affected cellular metabolism. These metabolic changes were mediated, in part, through differential expression of Myc, a transcription factor that controls glycolysis and metabolic reprogramming. Taken together, these results demonstrate that proteasome activity is an important regulator of CD8⁺ T cell fate and raise the possibility that increasing proteasome activity may be a useful therapeutic strategy to enhance the generation of memory lymphocytes.

中文翻译：

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蛋白酶体活性调节 CD8+ T 淋巴细胞代谢和命运规范

在免疫反应过程中，CD8 ⁺ T 淋巴细胞可以进行不对称分裂，产生子细胞，这些子细胞表现出采用终末效应细胞和记忆细胞命运的独特倾向。在这里，我们表明，体内第一次 CD8 ⁺ T 细胞分裂产生的“前效应细胞”和“前记忆细胞”分别表现出低和高的内源蛋白酶体活性。在分化早期， CD8 ⁺ T细胞中蛋白酶体活性的药理学降低导致了终末效应细胞特征的获得，而蛋白酶体活性的增强赋予了记忆淋巴细胞的属性。转录组学和蛋白质组学分析表明，调节 CD8 ⁺ T 细胞中的蛋白酶体活性会影响细胞代谢。这些代谢变化部分是通过 Myc 的差异表达介导的，Myc 是一种控制糖酵解和代谢重编程的转录因子。总而言之，这些结果表明蛋白酶体活性是 CD8 ⁺ T 细胞命运的重要调节剂，并提出了增加蛋白酶体活性可能是增强记忆淋巴细胞生成的有用治疗策略的可能性。