美国宾夕法尼亚大学E. John Wherry团队近期取得重要工作进展，他们通过时间性单细胞转录组学和表观遗传学揭示了效应型、记忆型和耗竭型CD8⁺ T细胞中共同和独特的生物回路。相关论文2022年10月21日在线发表于《自然—免疫学》杂志上。

研究人员利用淋巴细胞性绒毛膜炎病毒的急性溶解和慢性感染模型，通过应用纵向单细胞RNA测序（scRNA-seq）和单细胞检测转座酶可及染色质测序（scATAC-seq）分析来填补这些空白。研究人员发现了新的亚群，包括表达自然杀伤细胞相关基因的T_ex细胞亚群，它依赖于转录因子Zeb2，以及急性和慢性感染中多个不同的TCF-1⁺干/祖细胞样亚群。这些数据还揭示了程序性死亡1（PD-1）途径阻断后T_ex亚群的重塑，并确定了细胞压力调节器Btg1在建立T_ex群体中的关键作用。最后，这些结果强调了相同的生物回路（如细胞毒性或干细胞/祖细胞通路）如何被CD8⁺T细胞亚群使用，这些亚群在不同的感染过程中产生了高度不同的基础染色质图谱。

据介绍，Naïve CD8⁺ T细胞可分化为效应T细胞（T_eff）、记忆T细胞（T_mem）或耗竭T细胞（T_ex）。这些发育途径与不同的转录和表观遗传变化有关，这些变化赋予细胞不同的功能，因此具有治疗潜力。这些发育轨迹背后的分子机制以及T_eff、T_mem和T_ex种群内的异质性程度仍然知之甚少。

附：英文原文

Title: Shared and distinct biological circuits in effector, memory and exhausted CD8+ T cells revealed by temporal single-cell transcriptomics and epigenetics

Author: Giles, Josephine R., Ngiow, Shin Foong, Manne, Sasikanth, Baxter, Amy E., Khan, Omar, Wang, Ping, Staupe, Ryan, Abdel-Hakeem, Mohamed S., Huang, Hua, Mathew, Divij, Painter, Mark M., Wu, Jennifer E., Huang, Yinghui Jane, Goel, Rishi R., Yan, Patrick K., Karakousis, Giorgos C., Xu, Xiaowei, Mitchell, Tara C., Huang, Alexander C., Wherry, E. John

Issue&Volume: 2022-10-21

Abstract: Nave CD8+ T cells can differentiate into effector (Teff), memory (Tmem) or exhausted (Tex) T cells. These developmental pathways are associated with distinct transcriptional and epigenetic changes that endow cells with different functional capacities and therefore therapeutic potential. The molecular circuitry underlying these developmental trajectories and the extent of heterogeneity within Teff, Tmem and Tex populations remain poorly understood. Here, we used the lymphocytic choriomeningitis virus model of acute-resolving and chronic infection to address these gaps by applying longitudinal single-cell RNA-sequencing (scRNA-seq) and single-cell assay for transposase-accessible chromatin sequencing (scATAC-seq) analyses. These analyses uncovered new subsets, including a subpopulation of Tex cells expressing natural killer cell-associated genes that is dependent on the transcription factor Zeb2, as well as multiple distinct TCF-1+ stem/progenitor-like subsets in acute and chronic infection. These data also revealed insights into the reshaping of Tex subsets following programmed death 1 (PD-1) pathway blockade and identified a key role for the cell stress regulator, Btg1, in establishing the Tex population. Finally, these results highlighted how the same biological circuits such as cytotoxicity or stem/progenitor pathways can be used by CD8+ T cell subsets with highly divergent underlying chromatin landscapes generated during different infections.

DOI: 10.1038/s41590-022-01338-4

Source: https://www.nature.com/articles/s41590-022-01338-4