美国宾夕法尼亚大学E. John Wherry课题组通过四个耗竭CD8 ⁺ T细胞亚群的发育关系，揭示了潜在的转录和表观遗传调控机制。2020年5月11日，《免疫》在线发表了这一成果。

研究人员为耗竭CD8 ⁺ T细胞（Tex）定义了一个四细胞发育框架。研究人员鉴定了两个TCF1 ⁺祖细胞子集，一个受限于组织且处于静止状态，另外一个可进入血液且随细胞分裂而逐渐丢失TCF1并转化为第三个中间Tex子集。该中间子集重新参与了一些效应生物学，并在PD-L1阻断后增加，但最终转化为第四个末端耗竭的子集。

通过使用转录和表观遗传学分析，研究人员确定了子集转换的基础调控机制，并在此过程中定义了TCF1、T-bet和Tox之间的关键相互作用。这些数据揭示了Tex细胞的四个发育阶段，可能为改善癌症免疫疗法提供了分子、转录和表观遗传基础。

据介绍，CD8 ⁺ T细胞衰竭是当前抗肿瘤免疫疗法的主要障碍。尽管如此，耗竭CD8 ⁺ T细胞的发育生物学仍然不明确，限制了旨在“重新振兴” Tex细胞策略的改进。

附：英文原文

Title: Developmental Relationships of Four Exhausted CD8+ T Cell Subsets Reveals Underlying Transcriptional and Epigenetic Landscape Control Mechanisms

Author: Jean-Christophe Beltra, Sasikanth Manne, Mohamed S. Abdel-Hakeem, Makoto Kurachi, Josephine R. Giles, Zeyu Chen, Valentina Casella, Shin Foong Ngiow, Omar Khan, Yinghui Jane Huang, Patrick Yan, Kito Nzingha, Wei Xu, Ravi K. Amaravadi, Xiaowei Xu, Giorgos C. Karakousis, Tara C. Mitchell, Lynn M. Schuchter, Alexander C. Huang, E. John Wherry

Issue&Volume: 2020-05-11

Abstract: CD8+ T cell exhaustion is a major barrier to current anti-cancer immunotherapies. Despitethis, the developmental biology of exhausted CD8+ T cells (Tex) remains poorly defined, restraining improvement of strategies aimedat “re-invigorating” Tex cells. Here, we defined a four-cell-stage developmental frameworkfor Tex cells. Two TCF1+ progenitor subsets were identified, one tissue restricted and quiescent and one moreblood accessible, that gradually lost TCF1 as it divided and converted to a thirdintermediate Tex subset. This intermediate subset re-engaged some effector biologyand increased upon PD-L1 blockade but ultimately converted into a fourth, terminallyexhausted subset. By using transcriptional and epigenetic analyses, we identifiedthe control mechanisms underlying subset transitions and defined a key interplay betweenTCF1, T-bet, and Tox in the process. These data reveal a four-stage developmentalhierarchy for Tex cells and define the molecular, transcriptional, and epigeneticmechanisms that could provide opportunities to improve cancer immunotherapy.

DOI: 10.1016/j.immuni.2020.04.014

Source: https://www.cell.com/immunity/fulltext/S1074-7613(20)30172-2