Computational and Systems Biology Program, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA.
Howard Hughes Medical Institute and Immunology Program, Sloan Kettering Institute, and Ludwig Center at Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA.
Mol Cell. 2021 Jun 3;81(11):2477-2493.e10. doi: 10.1016/j.molcel.2021.03.045. Epub 2021 Apr 22.
CD8 T cells play an essential role in defense against viral and bacterial infections and in tumor immunity. Deciphering T cell loss of functionality is complicated by the conspicuous heterogeneity of CD8 T cell states described across experimental and clinical settings. By carrying out a unified analysis of over 300 assay for transposase-accessible chromatin sequencing (ATAC-seq) and RNA sequencing (RNA-seq) experiments from 12 studies of CD8 T cells in cancer and infection, we defined a shared differentiation trajectory toward dysfunction and its underlying transcriptional drivers and revealed a universal early bifurcation of functional and dysfunctional T cell states across models. Experimental dissection of acute and chronic viral infection using single-cell ATAC (scATAC)-seq and allele-specific single-cell RNA (scRNA)-seq identified state-specific drivers and captured the emergence of similar TCF1 progenitor-like populations at an early branch point, at which functional and dysfunctional T cells diverge. Our atlas of CD8 T cell states will facilitate mechanistic studies of T cell immunity and translational efforts.
CD8 T 细胞在防御病毒和细菌感染以及肿瘤免疫中发挥着至关重要的作用。由于在实验和临床环境中描述的 CD8 T 细胞状态具有明显的异质性，因此破译 T 细胞功能丧失的机制变得复杂。通过对来自癌症和感染中 12 项 CD8 T 细胞研究的超过 300 项转座酶可及染色质测序 (ATAC-seq) 和 RNA 测序 (RNA-seq) 实验进行统一分析，我们定义了一条向功能障碍和其潜在转录驱动因素分化的共享轨迹，并揭示了在不同模型中功能和功能障碍 T 细胞状态的普遍早期分支。使用单细胞 ATAC（scATAC）-seq 和等位基因特异性单细胞 RNA（scRNA）-seq 对急性和慢性病毒感染进行的实验剖析确定了特定状态的驱动因素，并在早期分支点捕获了类似 TCF1 祖细胞样群体的出现，在这个分支点，功能和功能障碍的 T 细胞开始分化。我们的 CD8 T 细胞状态图谱将有助于 T 细胞免疫的机制研究和转化努力。
