耗竭T细胞的表观遗传痕迹阻碍消除慢性抗原刺激

作者：张馨予

本期文章：《自然—免疫学》：Online/在线发表

近日，美国宾夕法尼亚大学E. John Wherry及其课题组发现，耗竭T细胞的表观遗传痕迹阻碍消除慢性抗原刺激后的记忆分化。2021年7月26日出版的《自然—免疫学》发表了这项成果。

据研究人员介绍，耗竭的CD8 T细胞（TEX）是T细胞分化的一种独特状态，与未能清除的慢性病毒和癌症有关。PD-1阻断等免疫疗法可使TEX细胞恢复活力，但恢复活力并不持久。一个主要的未解之谜是TEX细胞是否在清除抗原后分化为功能性的持久记忆T细胞（TMEM）。

通过使用一个小鼠模型，研究人员发现在消除慢性抗原刺激后，TEX细胞部分（重新）获得TMEM细胞的表型和转录特征。这些"恢复的"TEX细胞源自T细胞因子（TCF-1+）TEX祖先亚群。然而，与TMEM细胞相比，这些恢复的TEX细胞的记忆能力仍然受到损害。染色质可及性分析显示，其未能恢复核心记忆表观遗传回路，并维持了一个基本耗竭的开放染色质状态。因此，尽管抗原清除后有一些表型和转录的恢复，但耗竭会留下持久的表观遗传痕迹，从而制约以后的免疫反应。这些结果支持表观遗传重塑对TEX细胞靶向免疫疗法的干预。

附：英文原文

Title: Epigenetic scarring of exhausted T cells hinders memory differentiation upon eliminating chronic antigenic stimulation

Author: Mohamed S. Abdel-Hakeem, Sasikanth Manne, Jean-Christophe Beltra, Erietta Stelekati, Zeyu Chen, Kito Nzingha, Mohammed-Alkhatim Ali, John L. Johnson, Josephine R. Giles, Divij Mathew, Allison R. Greenplate, Golnaz Vahedi, E. John Wherry

Issue&Volume: 2021-07-26

Abstract: Exhausted CD8 T cells (TEX) are a distinct state of T cell differentiation associated with failure to clear chronic viruses and cancer. Immunotherapies such as PD-1 blockade can reinvigorate TEX cells, but reinvigoration is not durable. A major unanswered question is whether TEX cells differentiate into functional durable memory T cells (TMEM) upon antigen clearance. Here, using a mouse model, we found that upon eliminating chronic antigenic stimulation, TEX cells partially (re)acquire phenotypic and transcriptional features of TMEM cells. These ‘recovering’ TEX cells originated from the T cell factor (TCF-1+) TEX progenitor subset. Nevertheless, the recall capacity of these recovering TEX cells remained compromised as compared to TMEM cells. Chromatin-accessibility profiling revealed a failure to recover core memory epigenetic circuits and maintenance of a largely exhausted open chromatin landscape. Thus, despite some phenotypic and transcriptional recovery upon antigen clearance, exhaustion leaves durable epigenetic scars constraining future immune responses. These results support epigenetic remodeling interventions for TEX cell–targeted immunotherapies.

DOI: 10.1038/s41590-021-00975-5

Source: https://www.nature.com/articles/s41590-021-00975-5

期刊信息

Nature Immunology：《自然—免疫学》，创刊于2000年。隶属于施普林格·自然出版集团，最新IF：23.53
官方网址：https://www.nature.com/ni/
投稿链接：https://mts-ni.nature.com/cgi-bin/main.plex