Single-cell RNA-seq and computational analysis using temporal mixture modelling resolves Th1/Tfh fate bifurcation in malaria
| Autor: | Lam-Ha Ly, Max Zwiessele, Arya Sheela Nair, Daniel Fernandez-Ruiz, Ashraful Haque, Sarah A. Teichmann, Valentine Svensson, Urijah N. Liligeto, Michael J. T. Stubbington, Megan S. F. Soon, Fernando Souza-Fonseca-Guimaraes, Lily Fogg, Christian R. Engwerda, Patrick T. Bunn, Oliver Billker, Oliver Stegle, William R. Heath, Ruddy Montandon, Tapio Lönnberg, Kylie R. James, Neil D. Lawrence, Frederik Otzen Bagger, Ismail Sebina |
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| Přispěvatelé: | Bagger, Frederik [0000-0003-0636-8845], Lawrence, Neil David [0000-0001-9258-1030], Teichmann, Sarah [0000-0002-6294-6366], Apollo - University of Cambridge Repository |
| Jazyk: | angličtina |
| Rok vydání: | 2017 |
| Předmět: |
0301 basic medicine
T cell Cellular differentiation 1.1 Normal biological development and functioning Immunology Population 3207 Medical Microbiology 32 Biomedical and Clinical Sciences Biology FOS: Health sciences Bioinformatics Article Transcriptome 03 medical and health sciences Chemokine receptor 0302 clinical medicine Gene expression medicine Genetics 1 Underpinning research education Transcription factor education.field_of_study Inflammatory and immune system T-cell receptor Human Genome 3 Good Health and Well Being General Medicine 3. Good health Cell biology 3204 Immunology 030104 developmental biology medicine.anatomical_structure Infectious Diseases 030220 oncology & carcinogenesis FOS: Biological sciences Biotechnology |
| Zdroj: | Science Immunology |
| ISSN: | 2470-9468 |
| Popis: | Differentiation of naïve CD4+ T cells into functionally distinct T helper (TH) subsets is crucial for the orchestration of immune responses. Because of extensive heterogeneity and multiple overlapping transcriptional programs in differentiating T cell populations, this process has remained a challenge for systematic dissection in vivo. By using single-cell transcriptomics and computational analysis with a temporal mixtures of Gaussian processes model, termed GPfates, we reconstructed the developmental trajectories of TH1 and TFH (T follicular helper) cells during blood-stage Plasmodium infection in mice. By tracking clonality using endogenous T cell receptor sequences, we first demonstrated that TH1/TFH bifurcation had occurred at both population and single-clone levels. Next, we identified genes whose expression was associated with TH1 or TFH fates and demonstrated a T cell–intrinsic role for Galectin-1 in supporting TH1 differentiation. We also revealed the close molecular relationship between TH1 and interleukin-10–producing Tr1 cells in this infection. TH1 and TFH fates emerged from a highly proliferative precursor that up-regulated aerobic glycolysis and accelerated cell cycling as cytokine expression began. Dynamic gene expression of chemokine receptors around bifurcation predicted roles for cell-cell interaction in driving TH1/TFH fates. In particular, we found that precursor TH cells were coached toward a TH1 but not a TFH fate by inflammatory monocytes. Thus, by integrating genomic and computational approaches, our study has provided two unique resources: a database, www.PlasmoTH.org, which facilitates discovery of novel factors controlling TH1/TFH fate commitment, and, more generally, GPfates, a modeling framework for characterizing cell differentiation toward multiple fates. |
| Databáze: | OpenAIRE |
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