Elucidating T Cell Activation-Dependent Mechanisms for Bifurcation of Regulatory and Effector T Cell Differentiation by Multidimensional and Single-Cell Analysis
TLDR
This study reveals the activation mechanisms downstream of TCR signals for the bifurcation of Treg and Teff differentiation and their maturation processes.Abstract:
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 naive T cells, the relationship between Treg and non-naive 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.read more
Citations
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Dissecting the multicellular ecosystem of metastatic melanoma by single-cell RNA-seq
Itay Tirosh,Benjamin Izar,Daniel J. Treacy,John J. Trombetta,Asaf Rotem,Christopher Rodman,Christine G. Lian,George F. Murphy,Mohammad Fallahi-Sichani,Ken Dutton-Regester,Jia-Ren Lin,Ofir Cohen,Parin Shah,Diana Lu,Alexandra-Chloé Villani,Aleksandr Andreev,E.M. Van Allen,Monica M. Bertagnolli,Peter K. Sorger,Ryan J. Sullivan,Keith T. Flaherty,Dennie T. Frederick,Judit Jané-Valbuena,Orit Rozenblatt-Rosen,Sanjay M. Prakadan,Marc H. Wadsworth,Alex S. Genshaft,Travis K. Hughes,Carly G. K. Ziegler,Samuel W. Kazer,Alethe Gaillard de Saint Germain,Kellie E. Kolb,Cory M. Johannessen,Clifford H. Yoon,Alex K. Shalek,Aviv Regev,Levi A. Garraway +36 more
TL;DR: Tirosh et al. as discussed by the authors applied single-cell RNA sequencing (RNA-seq) to 4645 single cells isolated from 19 patients, profiling malignant, immune, stromal, and endothelial cells.
Journal ArticleDOI
T-Cell Hyperactivation and Paralysis in Severe COVID-19 Infection Revealed by Single-Cell Analysis.
Bahire Kalfaoglu,José Almeida-Santos,José Almeida-Santos,Chanidapa Adele Tye,Yorifumi Satou,Masahiro Ono,Masahiro Ono +6 more
TL;DR: This study proposes a new model of T-cell hyperactivation and paralysis that drives immunopathology in severe COVID-19, and shows single cell-level mechanisms for T- cell dysregulation in severeCOVID- 19, demonstrating new pathogenetic mechanisms of T -cell activation and differentiation underlying severe CO VID-19.
Journal ArticleDOI
Control of regulatory T-cell differentiation and function by T-cell receptor signalling and Foxp3 transcription factor complexes.
TL;DR: The current understanding of how Foxp3 transcription factor complexes regulate the differentiation, maintenance and functional maturation of Treg is shown, including TCR signal‐induced transcriptional and epigenetic mechanisms.
Posted ContentDOI
T-cell hyperactivation and paralysis in severe COVID-19 infection revealed by single-cell analysis
Bahire Kalfaoglu,José Almeida-Santos,José Almeida-Santos,Chanidapa Adele Tye,Yorifumi Satou,Masahiro Ono,Masahiro Ono +6 more
TL;DR: This study proposes a new model of T-cell hyperactivation and paralysis that drives pulmonary damage, systemic CRS and organ failure in severe COVID-19 patients.
Journal ArticleDOI
Th1 polarization defines the synovial fluid T cell compartment in oligoarticular juvenile idiopathic arthritis
Amélie M Julé,Kacie J Hoyt,Kevin Wei,Maria Gutierrez-Arcelus,Maria L. Taylor,Julie Ng,James A. Lederer,Siobhan M. Case,Margaret H. Chang,Ezra M. Cohen,Fatma Dedeoglu,Melissa M. Hazen,Jonathan S. Hausmann,Olha Halyabar,Erin Janssen,Jeffrey Lo,Mindy S. Lo,Esra Meidan,Jordan E Roberts,Mary Beth F. Son,Robert P. Sundel,Pui Y. Lee,Talal A. Chatila,Peter A. Nigrovic,Lauren A. Henderson +24 more
TL;DR: In this article, immunophenotyped synovial fluid T cells with flow cytometry, bulk RNA-seq, single-cell RNA-Seq, DNA methylation studies, and Treg suppression assays were used to understand immune responses in oligo juvenile idiopathic arthritis.
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Dissecting the multicellular ecosystem of metastatic melanoma by single-cell RNA-seq
Itay Tirosh,Benjamin Izar,Benjamin Izar,Sanjay M. Prakadan,Marc H. Wadsworth,Daniel J. Treacy,John J. Trombetta,Asaf Rotem,Asaf Rotem,Christopher Rodman,Christine G. Lian,George F. Murphy,Mohammad Fallahi-Sichani,Ken Dutton-Regester,Ken Dutton-Regester,Ken Dutton-Regester,Jia-Ren Lin,Ofir Cohen,Parin Shah,Diana Lu,Alex S. Genshaft,Travis K. Hughes,Carly G. K. Ziegler,Samuel W. Kazer,Aleth Gaillard,Kellie E. Kolb,Alexandra-Chloé Villani,Cory M. Johannessen,Aleksandr Andreev,Eliezer M. Van Allen,Eliezer M. Van Allen,Monica M. Bertagnolli,Monica M. Bertagnolli,Peter K. Sorger,Ryan J. Sullivan,Keith T. Flaherty,Dennie T. Frederick,Judit Jané-Valbuena,Charles H. Yoon,Charles H. Yoon,Orit Rozenblatt-Rosen,Alex K. Shalek,Aviv Regev,Aviv Regev,Aviv Regev,Levi A. Garraway +45 more
TL;DR: The cellular ecosystem of tumors is begin to unravel and how single-cell genomics offers insights with implications for both targeted and immune therapies is unraveled.