T cell exhaustion is associated with failure to clear chronic infections and malignant cells. Defining the molecular mechanisms of T cell exhaustion and reinvigoration is essential to improving immunotherapeutic modalities. Here we confirmed pervasive phenotypic, functional and transcriptional differences between memory and exhausted antigen-specific CD8⁺ T cells in human hepatitis C virus (HCV) infection before and after treatment. After viral cure, phenotypic changes in clonally stable exhausted T cell populations suggested differentiation toward a memory-like profile. However, functionally, the cells showed little improvement, and critical transcriptional regulators remained in the exhaustion state. Notably, T cells from chronic HCV infection that were exposed to antigen for less time because of viral escape mutations were functionally and transcriptionally more similar to memory T cells from spontaneously resolved HCV infection. Thus, the duration of T cell stimulation impacts exhaustion recovery, with antigen removal after long-term exhaustion being insufficient for the development of functional T cell memory.

T 细胞衰竭与未能清除慢性感染和恶性细胞有关。定义 T 细胞耗竭和恢复活力的分子机制对于改善免疫治疗方式至关重要。^{在这里，我们证实了记忆和耗尽的抗原特异性 CD8 +}之间普遍存在的表型、功能和转录差异治疗前后人类丙型肝炎病毒 (HCV) 感染中的 T 细胞。病毒治愈后，克隆稳定的衰竭 T 细胞群的表型变化表明分化为类似记忆的特征。然而，在功能上，细胞几乎没有改善，关键的转录调节因子仍处于衰竭状态。值得注意的是，由于病毒逃逸突变而暴露于抗原的时间较短的慢性 HCV 感染的 T 细胞在功能和转录上更类似于来自自发消退的 HCV 感染的记忆 T 细胞。因此，T 细胞刺激的持续时间会影响衰竭恢复，长期衰竭后的抗原去除不足以发展功能性 T 细胞记忆。