TCF-1-Centered Transcriptional Network Drives an Effector versus Exhausted CD8 T Cell-Fate Decision.,Immunity

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TCF-1-Centered Transcriptional Network Drives an Effector versus Exhausted CD8 T Cell-Fate Decision.
Immunity ( IF 25.5 ) Pub Date : 2019-10-09 , DOI: 10.1016/j.immuni.2019.09.013
Zeyu Chen ₁ , Zhicheng Ji ₂ , Shin Foong Ngiow ₁ , Sasikanth Manne ₁ , Zhangying Cai ₁ , Alexander C Huang ₃ , John Johnson ₄ , Ryan P Staupe ₁ , Bertram Bengsch ₁ , Caiyue Xu ₅ , Sixiang Yu ₆ , Makoto Kurachi ₁ , Ramin S Herati ₃ , Laura A Vella ₇ , Amy E Baxter ₁ , Jennifer E Wu ₁ , Omar Khan ₁ , Jean-Christophe Beltra ₁ , Josephine R Giles ₁ , Erietta Stelekati ₁ , Laura M McLane ₁ , Chi Wai Lau ₁ , Xiaolu Yang ₆ , Shelley L Berger ₅ , Golnaz Vahedi ₈ , Hongkai Ji ₂ , E John Wherry ₉

Affiliation

Department of Systems Pharmacology and Translational Therapeutics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA; Institute for Immunology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA.
Department of Biostatistics, Johns Hopkins Bloomberg School of Public Health, Baltimore, MD 21205, USA.
Department of Systems Pharmacology and Translational Therapeutics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA; Institute for Immunology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA; Department of Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA.
Institute for Immunology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA.
Department of Cell and Developmental Biology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA; Epigenetics Institute, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA.
Department of Cancer Biology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA.
Department of Systems Pharmacology and Translational Therapeutics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA; Institute for Immunology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA; Department of Pediatrics, Children's Hospital of Philadelphia, Philadelphia, PA 19104, USA.
Institute for Immunology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA; Epigenetics Institute, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA; Department of Genetics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA.
Department of Systems Pharmacology and Translational Therapeutics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA; Institute for Immunology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA; Parker Institute for Cancer Immunotherapy at University of Pennsylvania, Philadelphia, PA 19104, USA.

TCF-1 is a key transcription factor in progenitor exhausted CD8 T cells (Tex). Moreover, this Tex cell subset mediates responses to PD-1 checkpoint pathway blockade. However, the role of the transcription factor TCF-1 in early fate decisions and initial generation of Tex cells is unclear. Single-cell RNA sequencing (scRNA-seq) and lineage tracing identified a TCF-1+Ly108+PD-1+ CD8 T cell population that seeds development of mature Tex cells early during chronic infection. TCF-1 mediated the bifurcation between divergent fates, repressing development of terminal KLRG1Hi effectors while fostering KLRG1Lo Tex precursor cells, and PD-1 stabilized this TCF-1+ Tex precursor cell pool. TCF-1 mediated a T-bet-to-Eomes transcription factor transition in Tex precursors by promoting Eomes expression and drove c-Myb expression that controlled Bcl-2 and survival. These data define a role for TCF-1 in early-fate-bifurcation-driving Tex precursor cells and also identify PD-1 as a protector of this early TCF-1 subset.

中文翻译：

以 TCF-1 为中心的转录网络驱动效应器与耗尽 CD8 T 细胞的命运决定。

TCF-1 是祖细胞耗尽的 CD8 T 细胞 (Tex) 中的关键转录因子。此外，该 Tex 细胞亚群介导对 PD-1 检查点通路阻断的反应。然而，转录因子 TCF-1 在 Tex 细胞早期命运决定和初始生成中的作用尚不清楚。单细胞 RNA 测序 (scRNA-seq) 和谱系追踪鉴定出 TCF-1+Ly108+PD-1+ CD8 T 细胞群，该细胞群在慢性感染早期为成熟 Tex 细胞的发育提供种子。TCF-1 介导不同命运之间的分歧，抑制末端 KLRG1Hi 效应子的发育，同时培养 KLRG1Lo Tex 前体细胞，而 PD-1 稳定了该 TCF-1+ Tex 前体细胞库。TCF-1 通过促进 Eomes 表达并驱动控制 Bcl-2 和存活的 c-Myb 表达来介导 Tex 前体中的 T-bet-to-Eomes 转录因子转变。这些数据定义了 TCF-1 在早期命运分叉驱动 Tex 前体细胞中的作用，并确定 PD-1 作为该早期 TCF-1 子集的保护者。

更新日期：2019-10-10

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