CD8⁺ T cells responding to chronic infections or tumors acquire an ‘exhausted’ state associated with elevated expression of inhibitory receptors, including PD-1, and impaired cytokine production. Exhausted T cells are continuously replenished by T cells with precursor characteristics that self-renew and depend on the transcription factor TCF1; however, their developmental requirements are poorly understood. In the present study, we demonstrate that high antigen load promoted the differentiation of precursor T cells, which acquired hallmarks of exhaustion within days of infection, whereas early effector cells retained polyfunctional features. Early precursor T cells showed epigenetic imprinting characteristic of T cell receptor–dependent transcription factor binding and were restricted to the generation of cells displaying exhaustion characteristics. Transcription factors BACH2 and BATF were key regulators with opposing functions in the generation of early precursor T cells. Overall, we demonstrate that exhaustion manifests first in TCF1⁺ precursor T cells and is propagated subsequently to the pool of antigen-specific T cells.

CD8 ⁺对慢性感染或肿瘤有反应的T细胞获得“疲惫”状态，这种状态与抑制性受体（包括PD-1）的表达升高和细胞因子产生受损有关。耗尽的T细胞不断被具有自我更新且依赖于转录因子TCF1的前体特征的T细胞补充。但是，他们的发展要求了解得很少。在本研究中，我们证明了高抗原负载促进了前体T细胞的分化，该前体T细胞在感染后数天内获得了精疲力竭的标志，而早期效应细胞则保留了多功能功能。早期的前体T细胞表现出T细胞受体依赖性转录因子结合的表观遗传印记特征，并且仅限于显示衰竭特征的细胞的生成。转录因子BACH2和BATF是在早期前体T细胞生成中具有相反功能的关键调控因子。总的来说，我们证明疲惫首先在TCF1中出现⁺前体T细胞，然后繁殖至抗原特异性T细胞库。