Single-cell RNA-seq and computational analysis using temporal mixture modelling resolves Th1/Tfh fate bifurcation in malaria

Tapio Lonnberg, Valentine Svensson, Kylie James, Daniel Fernandez-Ruiz (Corresponding Author), Ismail Sebina (Corresponding Author), Ruddy Montandon (Corresponding Author), Megan Soon (Corresponding Author), Lily Georgina Fogg (Corresponding Author), Arya Sheela Nair (Corresponding Author), Urijah Liligeto (Corresponding Author), Michael Stubbington (Corresponding Author), Lam-Ha Ly (Corresponding Author), Frederik Otzen Bagger (Corresponding Author), Max Zwiessele (Corresponding Author), Neil Lawrence (Corresponding Author), Fernando Souza-Fonesca-Guimaraes (Corresponding Author), Patrick Bunn (Corresponding Author), Christian Engwerda (Corresponding Author), William Heath (Corresponding Author), Oliver Billker (Corresponding Author)Ashraful Haque, Sarah Teichmann

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106 Citations (Scopus)

Abstract

Differentiation of naïve CD4+ T cells into functionally distinct T helper subsets is crucial for the orchestration of immune responses. Due to 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 using a temporal mixtures of Gaussian processes model, termed GPfates, we reconstructed the developmental trajectories of Th1 and Tfh cells during blood-stage Plasmodium infection in mice. By tracking clonality using endogenous TCR 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 a Th1 differentiation. We also revealed the close molecular relationship between Th1 and IL-10-producing Tr1 cells in this infection. Th1 and Tfh fates emerged from a highly proliferative precursor that upregulated aerobic glycolysis and accelerated cell cycling as cytokine expression began. Dynamic gene expression of chemokine receptors around bifurcation predicted roles for cell-cell in driving Th1/Tfh fates. In particular, we found that precursor Th cells were coached towards 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 modelling framework for characterizing cell differentiation towards multiple fates
Original languageEnglish
Article numbereaal2192
JournalScience Immunology
Volume2
Issue number9
DOIs
Publication statusPublished - 3 Mar 2017

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    Lonnberg, T., Svensson, V., James, K., Fernandez-Ruiz, D., Sebina, I., Montandon, R., Soon, M., Fogg, L. G., Sheela Nair, A., Liligeto, U., Stubbington, M., Ly, L-H., Otzen Bagger, F., Zwiessele, M., Lawrence, N., Souza-Fonesca-Guimaraes, F., Bunn, P., Engwerda, C., Heath, W., ... Teichmann, S. (2017). Single-cell RNA-seq and computational analysis using temporal mixture modelling resolves Th1/Tfh fate bifurcation in malaria. Science Immunology, 2(9), [eaal2192]. https://doi.org/10.1126/sciimmunol.aal2192