Single cell multi-omics reveals early elevated function and multiple fates within human progenitors of exhausted CD8+ T cells

T-cell exhaustion is a hallmark of hepatitis C virus (HCV) infection and limits protective immunity in chronic viral infections and cancer. Limited knowledge exists of the initial viral and immune dynamics that characterise exhaustion in humans. We studied longitudinal blood samples from a unique cohort of subjects with primary infection using single cell multi-omics to identify the functions and phenotypes of HCV-specific CD8+ T cells. Early elevated IFN-γ response against the transmitted virus was associated with the rate of immune escape, larger clonal expansion, and early onset of exhaustion. Irrespective of disease outcome we discovered heterogenous subsets of progenitors of exhaustion, based on the level of PD-1 expression and loss of AP-1 transcription factors. Intra clonal analysis revealed distinct trajectories with multiple fates and evolutionary plasticity of precursor cells. These findings challenge current paradigm on the contribution of CD8+ T cells to HCV disease outcome and provide data for future studies on T-cell differentiation in human infections. Longitudinally sampled single HCV-specific CD8+ human T cells

T细胞耗竭（T-cell exhaustion）是丙型肝炎病毒（HCV）感染的标志性病理特征，可在慢性病毒感染及癌症进程中削弱机体的保护性免疫功能。目前学界对人类体内以T细胞耗竭为特征的初始病毒与免疫动态变化机制仍知之甚少。本研究借助单细胞多组学技术，对一组独特的原发性HCV感染受试者的纵向血液样本展开分析，以明确HCV特异性CD8+ T细胞的功能与表型特征。针对传播毒株的干扰素-γ（IFN-γ）早期应答水平升高，与免疫逃逸速率、更显著的克隆扩增以及T细胞耗竭的过早发生密切相关。无论最终疾病结局如何，研究团队均基于PD-1表达水平与AP-1转录因子的缺失情况，鉴定出了异质性的T细胞耗竭前体亚群。克隆内分析揭示了前体细胞具有多条分化轨迹、多样命运走向以及进化可塑性。上述研究结果挑战了当前关于CD8+ T细胞对HCV疾病结局影响的主流认知范式，并为未来人类感染性疾病中T细胞分化的相关研究提供了数据支撑。纵向采集的单个HCV特异性人类CD8+ T细胞