The expansion of CD8⁺CD28^– T cells, a population of terminally differentiated memory T cells, is one of the most consistent immunological changes in humans during aging. CD8⁺CD28^– T cells are highly cytotoxic, and their frequency is linked to many age-related diseases. As they do not accumulate in mice, many of the molecular mechanisms regulating their fate and function remain unclear. In this paper, we find that human CD8⁺CD28^– T cells, under resting conditions, have an enhanced capacity to use glycolysis, a function linked to decreased expression of the NAD⁺-dependent protein deacetylase SIRT1. Global gene expression profiling identified the transcription factor FoxO1 as a SIRT1 target involved in transcriptional reprogramming of CD8⁺CD28^– T cells. FoxO1 is proteasomally degraded in SIRT1-deficient CD8⁺CD28^– T cells, and inhibiting its activity in resting CD8⁺CD28⁺ T cells enhanced glycolytic capacity and granzyme B production as in CD8⁺CD28^– T cells. These data identify the evolutionarily conserved SIRT1–FoxO1 axis as a regulator of resting CD8⁺ memory T cell metabolism and activity in humans.

CD8 ⁺ CD28 ^- T细胞（一种最终分化的记忆T细胞）的扩增是人类衰老过程中最一致的免疫学变化之一。CD8 ⁺ CD28 ^– T细胞具有高度细胞毒性，其频率与许多与年龄有关的疾病有关。由于它们没有在小鼠体内积累，因此调节其命运和功能的许多分子机制仍不清楚。在本文中，我们发现人CD8 ⁺ CD28 ^- T细胞在静止条件下具有增强的糖酵解能力，这种功能与NAD ^+的表达降低有关。依赖性蛋白脱乙酰基酶SIRT1。全球基因表达谱鉴定为转录因子FoxO1为SIRT1靶标，参与CD8 ⁺ CD28 ^– T细胞的转录重编程。FoxO1的是proteasomally降解在SIRT1缺陷型CD8 ⁺ CD28 ^- T细胞，并在休息CD8抑制其活性⁺ CD28 ⁺增强糖酵解能力和粒酶B的生产如在CD8 T细胞⁺ CD28 ^- T细胞。这些数据确定了进化上保守的SIRT1-FoxO1轴是调节人体内CD8 ⁺记忆T细胞代谢和活性的调节剂。