Exhausted CD8 T cells (T_EX) are a distinct state of T cell differentiation associated with failure to clear chronic viruses and cancer. Immunotherapies such as PD-1 blockade can reinvigorate T_EX cells, but reinvigoration is not durable. A major unanswered question is whether T_EX cells differentiate into functional durable memory T cells (T_MEM) upon antigen clearance. Here, using a mouse model, we found that upon eliminating chronic antigenic stimulation, T_EX cells partially (re)acquire phenotypic and transcriptional features of T_MEM cells. These ‘recovering’ T_EX cells originated from the T cell factor (TCF-1⁺) T_EX progenitor subset. Nevertheless, the recall capacity of these recovering T_EX cells remained compromised as compared to T_MEM cells. Chromatin-accessibility profiling revealed a failure to recover core memory epigenetic circuits and maintenance of a largely exhausted open chromatin landscape. Thus, despite some phenotypic and transcriptional recovery upon antigen clearance, exhaustion leaves durable epigenetic scars constraining future immune responses. These results support epigenetic remodeling interventions for T_EX cell–targeted immunotherapies.

耗尽的 CD8 T 细胞 (T _EX ) 是 T 细胞分化的一种独特状态，与未能清除慢性病毒和癌症有关。PD-1 阻断等免疫疗法可以重振 T _EX细胞，但重振效果并不持久。一个未解决的主要问题是 T _EX细胞是否会在抗原清除后分化为功能性持久记忆 T 细胞 (T _{MEM )。}在这里，我们使用小鼠模型发现，在消除慢性抗原刺激后，T _EX细胞部分（重新）获得了 T _MEM细胞的表型和转录特征。这些“恢复”的 T _EX细胞源自 T 细胞因子 (TCF-1 ⁺ ) T _EX祖子集。_{然而，与 T MEM}细胞相比，这些恢复中的 T _EX细胞的召回能力仍然受到损害。染色质可及性分析显示未能恢复核心记忆表观遗传电路和维持很大程度上耗尽的开放染色质景观。因此，尽管抗原清除后有一些表型和转录恢复，但衰竭会留下持久的表观遗传疤痕，限制未来的免疫反应。这些结果支持 T _EX细胞靶向免疫疗法的表观遗传重塑干预。