Elucidating T Cell Activation-Dependent Mechanisms for Bifurcation of Regulatory and Effector T Cell Differentiation by Multidimensional and Single-Cell Analysis.
Elucidating T Cell Activation-Dependent Mechanisms for Bifurcation of Regulatory and Effector T Cell Differentiation by Multidimensional and Single-Cell Analysis.
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DOI：
10.3389/fimmu.2018.01444
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发表时间：
2018
影响因子：
7.3
通讯作者：
Ono M
中科院分区：
文献类型：
--
作者：
Bradley A;Hashimoto T;Ono M
在T细胞中，T细胞受体（TCR）信号传导启动T细胞活化和分化的下游转录机制。表达Foxp 3的调节性T细胞（Treg）需要TCR信号用于其在外周中的抑制性功能和维持。然而，TCR信号传导如何控制Treg的转录程序尚不清楚。由于大多数研究确定了Treg与幼稚T细胞相比的转录特征，Treg与非幼稚T细胞（包括记忆表型T细胞（T细胞）和效应T细胞（Teff））之间的关系尚不清楚。在这里，我们使用多维分析方法典型对应分析（CCA）从独立的数据集解剖各种T细胞亚群的转录组。我们表明，在细胞群体水平上，静息Treg与Teff和Teff共享用于激活的基因模块。重要的是，T细胞活化不同的转录模块用于T细胞活化，其在Treg中被独特地抑制。Treg的激活特征依赖于TCR信号，并且在激活的Treg中更活跃地起作用。此外，通过使用一种新的基于CCA的方法，单细胞组合CCA，我们分析了来自肿瘤浸润T细胞的未注释的单细胞RNA-seq数据，并揭示FOXP 3表达主要发生在活化的T细胞中。此外，我们在肿瘤微环境中鉴定了FOXP 3驱动的和T滤泡辅助细胞样分化途径，以及它们的分叉点，该分叉点富含最近活化的T细胞。总的来说，我们的研究揭示了TCR信号下游的活化机制，用于Treg和Teff分化及其成熟过程的分叉。
In T cells, T cell receptor (TCR) signaling initiates downstream transcriptional mechanisms for T cell activation and differentiation. Foxp3-expressing regulatory T cells (Treg) require TCR signals for their suppressive function and maintenance in the periphery. It is, however, unclear how TCR signaling controls the transcriptional program of Treg. Since most of studies identified the transcriptional features of Treg in comparison to naïve T cells, the relationship between Treg and non-naïve T cells including memory-phenotype T cells (Tmem) and effector T cells (Teff) is not well understood. Here, we dissect the transcriptomes of various T cell subsets from independent datasets using the multidimensional analysis method canonical correspondence analysis (CCA). We show that at the cell population level, resting Treg share gene modules for activation with Tmem and Teff. Importantly, Tmem activate the distinct transcriptional modules for T cell activation, which are uniquely repressed in Treg. The activation signature of Treg is dependent on TCR signals and is more actively operating in activated Treg. Furthermore, by using a new CCA-based method, single-cell combinatorial CCA, we analyzed unannotated single-cell RNA-seq data from tumor-infiltrating T cells, and revealed that FOXP3 expression occurs predominantly in activated T cells. Moreover, we identified FOXP3-driven and T follicular helper-like differentiation pathways in tumor microenvironments, and their bifurcation point, which is enriched with recently activated T cells. Collectively, our study reveals the activation mechanisms downstream of TCR signals for the bifurcation of Treg and Teff differentiation and their maturation processes.
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影响因子：
30.5
作者：
Cretney, Erika;Xin, Annie;Kallies, Axel
通讯作者：
Kallies, Axel
影响因子：
64.5
作者：
Dang EV;Barbi J;Yang HY;Jinasena D;Yu H;Zheng Y;Bordman Z;Fu J;Kim Y;Yen HR;Luo W;Zeller K;Shimoda L;Topalian SL;Semenza GL;Dang CV;Pardoll DM;Pan F
通讯作者：
Pan F
DOI：
10.1084/jem.176.6.1595
发表时间：
1992-12-01
期刊：
The Journal of experimental medicine
影响因子：
--
作者：
Linsley PS;Greene JL;Tan P;Bradshaw J;Ledbetter JA;Anasetti C;Damle NK
通讯作者：
Damle NK
影响因子：
46.9
作者：
Butler A;Hoffman P;Smibert P;Papalexi E;Satija R
通讯作者：
Satija R
DOI：
10.1073/pnas.1002006107
发表时间：
2010-03-30
影响因子：
11.1
作者：
Feuerer, Markus;Hill, Jonathan A.;Benoist, Christophe
通讯作者：
Benoist, Christophe