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dc.contributor.authorLonnberg, Tapio
dc.contributor.authorSvensson, Valentine
dc.contributor.authorJames, Kylie R
dc.contributor.authorFernandez-Ruiz, Daniel
dc.contributor.authorSebina, Ismail
dc.contributor.authorMontandon, Ruddy
dc.contributor.authorSoon, Megan SF
dc.contributor.authorFogg, Lily G
dc.contributor.authorNair, Arya Sheela
dc.contributor.authorLiligeto, Urijah N
dc.contributor.authorStubbington, Michael JT
dc.contributor.authorLy, Lam-Ha
dc.contributor.authorBagger, Frederik Otzen
dc.contributor.authorZwiessele, Max
dc.contributor.authorLawrence, Neil D
dc.contributor.authorSouza-Fonseca-Guimaraes, Fernando
dc.contributor.authorBunn, Patrick T
dc.contributor.authorEngwerda, Christian R
dc.contributor.authorHeath, William R
dc.contributor.authorBillker, Oliver
dc.contributor.authorStegle, Oliver
dc.contributor.authorHaque, Ashraful
dc.contributor.authorTeichmann, Sarah A
dc.date.accessioned2020-02-26T02:36:35Z
dc.date.available2020-02-26T02:36:35Z
dc.date.issued2017
dc.identifier.issn2470-9468
dc.identifier.doi10.1126/sciimmunol.aal2192
dc.identifier.urihttp://hdl.handle.net/10072/391917
dc.description.abstractDifferentiation 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.
dc.description.peerreviewedYes
dc.languageEnglish
dc.publisherAMER ASSOC ADVANCEMENT SCIENCE
dc.relation.ispartofissue9
dc.relation.ispartofjournalScience Immunology
dc.relation.ispartofvolume2
dc.subject.fieldofresearchImmunology
dc.subject.fieldofresearchcode1107
dc.subject.keywordsScience & Technology
dc.subject.keywordsLife Sciences & Biomedicine
dc.subject.keywordsImmunology
dc.subject.keywordsFOLLICULAR HELPER-CELL
dc.subject.keywordsCXC CHEMOKINE RECEPTOR-5
dc.titleSingle-cell RNA-seq and computational analysis using temporal mixture modeling resolves TH1/TFH fate bifurcation in malaria
dc.typeJournal article
dc.type.descriptionC1 - Articles
dcterms.bibliographicCitationLonnberg, T; Svensson, V; James, KR; Fernandez-Ruiz, D; Sebina, I; Montandon, R; Soon, MSF; Fogg, LG; Nair, AS; Liligeto, UN; Stubbington, MJT; Ly, L-H; Bagger, Engwerda, CR; et al. SA, Single-cell RNA-seq and computational analysis using temporal mixture modeling resolves T(H)1/T-FH fate bifurcation in malaria, Science Immunology, 2017, 2 (9)
dc.date.updated2020-02-26T02:26:55Z
dc.description.versionPost-print
gro.rights.copyright© The Author(s) 2017. This is the author’s version of the work. It is posted here by permission of the AAAS for personal use, not for redistribution. The definitive version was published in Science Signaling on Vol. 2, Issue 9, eaal2192, 2017, DOI: https://dx.doi.org/10.1126/sciimmunol.aal2192.
gro.hasfulltextFull Text
gro.griffith.authorEngwerda, Christian R.


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