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- Title
Single-cell RNA-seq and computational analysis using temporal mixture modeling resolves T<sub>H</sub>1/T<sub>FH</sub> fate bifurcation in malaria.
- Authors
Lönnberg, Tapio; Svensson, Valentine; James, Kylie R.; Fernandez-Ruiz, Daniel; Sebina, Ismail; Montandon, Ruddy; Soon, Megan S. F.; Fogg, Lily G.; Nair, Arya Sheela; Liligeto, Urijah N.; Stubbington, Michael J. T.; Lam-Ha Ly; Bagger, Frederik Otzen; Zwiessele, Max; Lawrence, Neil D.; Souza-Fonseca-Guimaraes, Fernando; Bunn, Patrick T.; Engwerda, Christian R.; Heath, William R.; Billker, Oliver
- Abstract
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.
- Subjects
MALARIA prevention; CYTOPROTECTION; SINGLE cell proteins; TRANSCRIPTION factors; RNA sequencing; T cells
- Publication
Science Immunology, 2017, Vol 2, Issue 9, p1
- ISSN
2470-9468
- Publication type
Article
- DOI
10.1126/sciimmunol.aal2192