Shared and distinct biological circuits in effector, memory and exhausted CD8(+) T cells revealed by temporal single-cell transcriptomics and epigenetics.
Shared and distinct biological circuits in effector, memory and exhausted CD8(+) T cells revealed by temporal single-cell transcriptomics and epigenetics.
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DOI：
10.1038/s41590-022-01338-4
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发表时间：
2022-11
影响因子：
30.5
通讯作者：
Wherry, E. John
中科院分区：
文献类型：
--
作者：
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
Naïve CD8+ T细胞可以分化为效应T细胞（Teff）、记忆T细胞（Tmem）或耗尽T细胞（Tex）。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能力，从而具有治疗潜力。这些发育轨迹背后的分子电路以及Teff、Tmem和Tex种群的异质性程度仍然知之甚少。在这里，我们使用淋巴细胞脉络丛脑膜炎病毒急性和慢性感染模型，通过纵向单细胞rna测序（scRNA-seq）和单细胞转座酶可及染色质测序（scATAC-seq）分析来解决这些差距。这些分析揭示了新的亚群，包括表达依赖于转录因子Zeb2的自然杀伤细胞相关基因的Tex细胞亚群，以及急性和慢性感染中的多个不同的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）通路阻断后Tex亚群的重塑，并确定了细胞应激调节因子Btg1在建立Tex群体中的关键作用。最后，这些结果强调了细胞毒性或干细胞/祖细胞途径等相同的生物回路如何被CD8+ T细胞亚群使用，这些细胞亚群在不同感染期间产生的潜在染色质景观高度不同。
Naïve 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.
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影响因子：
64.8
作者：
Im SJ;Hashimoto M;Gerner MY;Lee J;Kissick HT;Burger MC;Shan Q;Hale JS;Lee J;Nasti TH;Sharpe AH;Freeman GJ;Germain RN;Nakaya HI;Xue HH;Ahmed R
通讯作者：
Ahmed R
影响因子：
64.5
作者：
Good CR;Aznar MA;Kuramitsu S;Samareh P;Agarwal S;Donahue G;Ishiyama K;Wellhausen N;Rennels AK;Ma Y;Tian L;Guedan S;Alexander KA;Zhang Z;Rommel PC;Singh N;Glastad KM;Richardson MW;Watanabe K;Tanyi JL;O'Hara MH;Ruella M;Lacey SF;Moon EK;Schuster SJ;Albelda SM;Lanier LL;Young RM;Berger SL;June CH
通讯作者：
June CH
影响因子：
30.5
作者：
Kaech, SM;Tan, JT;Ahmed, R
通讯作者：
Ahmed, R
影响因子：
64.8
作者：
Khan, Omar;Giles, Josephine R.;Wherry, E. John
通讯作者：
Wherry, E. John
DOI：
10.1084/jem.20201730
发表时间：
2021-04-05
期刊：
The Journal of experimental medicine
影响因子：
--
作者：
Chung HK;McDonald B;Kaech SM
通讯作者：
Kaech SM