CD8⁺ T cells that respond to chronic viral infections or cancer are characterized by the expression of inhibitory receptors such as programmed cell death protein 1 (PD-1) and by the impaired production of cytokines. This state of restrained functionality—which is referred to as T cell exhaustion^1,2—is maintained by precursors of exhausted T (T_PEX) cells that express the transcription factor T cell factor 1 (TCF1), self-renew and give rise to TCF1⁻ exhausted effector T cells^3,4,5,6. Here we show that the long-term proliferative potential, multipotency and repopulation capacity of exhausted T cells during chronic infection are selectively preserved in a small population of transcriptionally distinct CD62L⁺ T_PEX cells. The transcription factor MYB is not only essential for the development of CD62L⁺ T_PEX cells and maintenance of the antiviral CD8⁺ T cell response, but also induces functional exhaustion and thereby prevents lethal immunopathology. Furthermore, the proliferative burst in response to PD-1 checkpoint inhibition originates exclusively from CD62L⁺ T_PEX cells and depends on MYB. Our findings identify CD62L⁺ T_PEX cells as a stem-like population that is central to the maintenance of long-term antiviral immunity and responsiveness to immunotherapy. Moreover, they show that MYB is a transcriptional orchestrator of two fundamental aspects of exhausted T cell responses: the downregulation of effector function and the long-term preservation of self-renewal capacity.

对慢性病毒感染或癌症有反应的CD8 ⁺ T 细胞的特点是表达抑制性受体，如程序性细胞死亡蛋白 1 (PD-1) 和细胞因子的产生受损。这种被称为 T 细胞衰竭^1,2的功能受限状态由表达转录因子 T 细胞因子 1 (TCF1)、自我更新并_产生TCF1 ^-耗尽的效应 T 细胞^3,4,5,6。在这里，我们表明，在慢性感染期间耗尽的 T 细胞的长期增殖潜力、多能性和再增殖能力在一小部分转录不同的 CD62L 中被选择性保留⁺ T _PEX细胞。转录因子 MYB 不仅对 CD62L ⁺ T _PEX细胞的发育和维持抗病毒 CD8 ⁺ T 细胞反应至关重要，而且还诱导功能衰竭，从而防止致命的免疫病理学。此外，响应于 PD-1 检查点抑制的增殖爆发完全源自 CD62L ⁺ T _PEX细胞并取决于 MYB。我们的发现确定了 CD62L ⁺ T _PEX细胞作为干细胞样群体，对于维持长期抗病毒免疫和对免疫治疗的反应至关重要。此外，他们表明 MYB 是耗尽 T 细胞反应的两个基本方面的转录协调器：效应器功能的下调和自我更新能力的长期保存。