TY - JOUR T1 - Temporal mixture modelling of single-cell RNA-seq data resolves a CD4<sup>+</sup> T cell fate bifurcation JF - bioRxiv DO - 10.1101/074971 SP - 074971 AU - Tapio Lönnberg AU - Valentine Svensson AU - Kylie R James AU - Daniel Fernandez-Ruiz AU - Ismail Sebina AU - Ruddy Montandon AU - Megan S. F. Soon AU - Lily G Fogg AU - Michael J. T. Stubbington AU - Frederik Otzen Bagger AU - Max Zwiessele AU - Neil Lawrence AU - Fernando Souza-Fonseca-Guimaraes AU - William R. Heath AU - Oliver Billker AU - Oliver Stegle AU - Ashraful Haque AU - Sarah A. Teichmann Y1 - 2016/01/01 UR - http://biorxiv.org/content/early/2016/09/13/074971.abstract N2 - 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. ER -