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Single cell multi-omics reveals early elevated function and multiple fates within human progenitor exhausted CD8+ T cells
bioRxiv - Immunology Pub Date : 2021-09-11 , DOI: 10.1101/2021.09.09.459584
Fabio Luciani , Jerome Samir , Preston Leung , Katherine Kedzierska , Tho Nguyen , Andrew Lloyd , Curtis Cai , Rowena Bull , Elizabeth Keoshkerian , Auda Eltahla , Timothy Peters , Silvana Gaudieri , Money Gupta , Thiruni Adikari , Raymond Louie , Simone Rizzetto , Willem Van der Byl , Mehdi Rasoli , Jean-Louis Palgen

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 progenitors of early-exhaustion with intermediate expression of PD-1. Intra clonal analysis revealed distinct trajectories with multiple fates suggesting 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.

中文翻译:

单细胞多组学揭示了人类祖细胞耗竭的 CD8+ T 细胞的早期功能升高和多种命运

T 细胞耗竭是丙型肝炎病毒 (HCV) 感染的标志,限制了慢性病毒感染和癌症的保护性免疫。关于表征人类衰竭的初始病毒和免疫动力学的知识有限。我们使用单细胞多组学研究了一组独特的原发性感染受试者的纵向血液样本,以确定 HCV 特异性 CD8 +的功能和表型T细胞。针对传播病毒的早期 IFN-γ 反应升高与免疫逃逸率、更大的克隆扩增和早期衰竭相关。无论疾病结果如何,我们都发现了具有 PD-1 中间表达的早期衰竭的祖细胞。克隆内分析揭示了具有多种命运的不同轨迹,表明前体细胞的进化可塑性。这些发现挑战了当前关于 CD8 + T 细胞对 HCV 疾病结果的贡献的范式,并为未来人类感染中 T 细胞分化的研究提供了数据。
更新日期:2021-09-14
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