RT Journal Article SR Electronic T1 Temporal mixture modelling of single-cell RNA-seq data resolves a CD4+ T cell fate bifurcation JF bioRxiv FD Cold Spring Harbor Laboratory SP 074971 DO 10.1101/074971 A1 Tapio Lönnberg A1 Valentine Svensson A1 Kylie R James A1 Daniel Fernandez-Ruiz A1 Ismail Sebina A1 Ruddy Montandon A1 Megan S. F. Soon A1 Lily G Fogg A1 Michael J. T. Stubbington A1 Frederik Otzen Bagger A1 Max Zwiessele A1 Neil Lawrence A1 Fernando Souza-Fonseca-Guimaraes A1 William R. Heath A1 Oliver Billker A1 Oliver Stegle A1 Ashraful Haque A1 Sarah A. Teichmann YR 2016 UL http://biorxiv.org/content/early/2016/09/13/074971.abstract AB 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.