Temporal mixture modelling of single-cell RNA-seq data resolves a CD4 + T cell fate bifurcation
Year: 2016
Type: preprint
Abstract: Differentiation of naïve CD4 + T cells into functionally distinct T helper subsets is crucial for the orchestration of immune responses. Due to multiple levels of 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 RNA transcriptomics and computational modelling of temporal mixtures, we reconstructed the developmental trajectories of Th1 and Tfh cell populations during Plasmodium infection in mice at single-cell resolution. These cell fates emerged from a common, highly proliferative and metabolically active precursor. Moreover, by tracking clonality from T cell receptor sequences, we infer that ancestors derived from the same naïve CD4 + T cell can concurrently populate both Th1 and Tfh subsets. We further found that precursor T cells were coached towards a Th1 but not a Tfh fate by monocytes/macrophages. The integrated genomic and computational approach we describe is applicable for analysis of any cellular system characterized by differentiation towards multiple fates. One Sentence Summary Using single-cell RNA sequencing and a novel unsupervised computational approach, we resolve the developmental trajectories of two CD4 + T cell fates in vivo , and show that uncommitted T cells are externally influenced towards one fate by inflammatory monocytes.
DOI: 10.1101/074971
Authors: Tapio Lönnberg, Valentine Svensson, Kylie R James, Daniel Fernandez-Ruiz, Ismail Sebina, Ruddy Montandon, Megan S. F. Soon, Lily G Fogg, Michael J. T. Stubbington, Frederik Otzen Bagger, Max Zwiessele, Neil Lawrence, Fernando Souza-Fonseca-Guimaraes, William R. Heath, Oliver Billker, Oliver Stegle, Ashraful Haque, Sarah A. Teichmann
Institutions: European Bioinformatics Institute, Wellcome Sanger Institute, European Molecular Biology Laboratory, QIMR Berghofer Medical Research Institute, The University of Melbourne, Peter Doherty Institute, National Health Service, NHS Blood and Transplant, University of Cambridge, University of Sheffield
Language: English
Subfield: Molecular Biology
Domain: Life Sciences
Open Access status: green
Funders: Wellcome Trust, QIMR Berghofer Medical Research Institute, EMBL Australia, Lister Institute of Preventive Medicine, Lundbeckfonden, H. Lundbeck A/S, Shanghai Key Laboratory of Materials Laser Processing and Modification, Shanghai Jiao Tong University, Medical Research Council, National Health and Medical Research Council, FP7 People: Marie-Curie Actions
OpenAlex ID: W2528023947