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Transcriptome dynamics of CD4⁺ T cells during malaria maps gradual transit from effector to memory

Soon, Megan S. F. and Lee, Hyun Jae and Engel, Jessica A. and Straube, Jasmin and Thomas, Bryce S. and Pernold, Clara P. S. and Clarke, Lachlan S. and Laohamonthonkul, Pawat and Haldar, Rohit N. and Williams, Cameron G. and Lansink, Lianne I. M. and Moreira, Marcela L. and Bramhall, Michael and Koufariotis, Lambros T. and Wood, Scott and Chen, Xi and James, Kylie R. and Lönnberg, Tapio and Lane, Steven W. and Belz, Gabrielle T. and Engwerda, Christian R. and Khoury, David S. and Davenport, Miles P. and Svensson, Valentine and Teichmann, Sarah A. and Haque, Ashraful (2020) Transcriptome dynamics of CD4⁺ T cells during malaria maps gradual transit from effector to memory. Nature Immunology, 21 (12). pp. 1597-1610. ISSN 1529-2908.

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[img] Image (JPEG) (Extended Data Fig. 1: PbTII cells localise to T cell zones, B cell follicles and GCs during infection) - Supplemental Material
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[img] Image (JPEG) (Extended Data Fig. 2: PbTII cells exhibit functional memory characteristics) - Supplemental Material
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[img] Image (JPEG) (Extended Data Fig. 3: PbTII cells at peak effector stage display mixed expression of canonical TH1 and TFH markers) - Supplemental Material
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[img] Image (JPEG) (Extended Data Fig. 4: Quality control checks for scRNA-seq assessment of memory PbTII cell differentiation) - Supplemental Material
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[img] Image (JPEG) (Extended Data Fig. 5: Multiple computational approaches for trajectory inference of PbTII scRNA-seq data) - Supplemental Material
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[img] Image (JPEG) (Extended Data Fig. 6: Gene expression and protein validation of multiple memory-associated genes in PbTII cells) - Supplemental Material
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[img] Image (JPEG) (Extended Data Fig. 7: Clonal analysis of memory fate and lineage plasticity testing with and without IAT) - Supplemental Material
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[img] Image (JPEG) (Extended Data Fig. 8: Assessing relationships of TH1 and Tfh-lineages with TCM, GC Tfh and Tr1 subsets in the GPfates model) - Supplemental Material
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[img] Image (JPEG) (Extended Data Fig. 9: Changes in availability of transcription factor binding motifs in memory PbTII cells via scATAC-seq) - Supplemental Material
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[img] Image (JPEG) (Extended Data Fig. 10: A conceptual view for development of memory CD4+ T cells during malaria) - Supplemental Material
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The dynamics of CD4⁺ T cell memory development remain to be examined at genome scale. In malaria-endemic regions, antimalarial chemoprevention protects long after its cessation and associates with effects on CD4⁺ T cells. We applied single-cell RNA sequencing and computational modelling to track memory development during Plasmodium infection and treatment. In the absence of central memory precursors, two trajectories developed as T helper 1 (T_H1) and follicular helper T (T_(FH)) transcriptomes contracted and partially coalesced over three weeks. Progeny of single clones populated T_H1 and T_(FH) trajectories, and fate-mapping suggested that there was minimal lineage plasticity. Relationships between T_(FH) and central memory were revealed, with antimalarials modulating these responses and boosting T_H1 recall. Finally, single-cell epigenomics confirmed that heterogeneity among effectors was partially reset in memory. Thus, the effector-to-memory transition in CD4⁺ T cells is gradual during malaria and is modulated by antiparasitic drugs. Graphical user interfaces are presented for examining gene-expression dynamics and gene–gene correlations (

Item Type:Article
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URLURL TypeDescription ReadCube access Paper ItemGraphical User Interfaces
Soon, Megan S. F.0000-0001-8563-849X
Engel, Jessica A.0000-0001-6175-1797
Straube, Jasmin0000-0002-1748-0659
Thomas, Bryce S.0000-0003-4770-5393
Clarke, Lachlan S.0000-0003-0342-9040
Laohamonthonkul, Pawat0000-0003-1261-1848
Lansink, Lianne I. M.0000-0003-1965-1287
Bramhall, Michael0000-0001-5938-158X
Koufariotis, Lambros T.0000-0002-4917-1375
Wood, Scott0000-0003-4543-8850
Chen, Xi0000-0003-2648-3146
James, Kylie R.0000-0002-7107-0650
Lönnberg, Tapio0000-0003-4484-5657
Belz, Gabrielle T.0000-0002-9660-9587
Engwerda, Christian R.0000-0003-2813-4804
Khoury, David S.0000-0002-2663-1551
Davenport, Miles P.0000-0002-4751-1831
Svensson, Valentine0000-0002-9217-2330
Teichmann, Sarah A.0000-0002-6294-6366
Haque, Ashraful0000-0003-2260-0026
Alternate Title:Transcriptome Dynamics Reveals Progressive Transition from Effector to Memory in CD4+ T cells, Transcriptome dynamics of CD4⁺ T cells during malaria maps gradual transit from effector to memory, Transcriptome Dynamics Reveals Progressive Transition from Effector to Memory in CD4⁺ T cells
Additional Information:© 2020 Nature Publishing Group. Received 12 February 2020; Accepted 28 August 2020; Published 12 October 2020. This study was funded by the Australian National Health & Medical Research Council: Project Grant 1126399 (awarded to A.H. and S.A.T.). Smart-seq2 work was funded by ERC Consolidator grant ThDEFINE (awarded to S.A.T.). We are grateful to J. Moehrle at Medicines for Malaria Venture for providing sodium artesunate. We acknowledge the expertise and assistance of several QIMR Berghofer Medical Research Institute Core Staff: the Flow Cytometry and Microscopy Core, particularly M. Rist and T. Hong Nguyen, for single-cell sorting; the Histology Core, including C. Winterford; the Animal Facility, including all technicians involved with animal husbandry; the Next-Generation-Sequencing Core, including P. Collins for assistance with droplet-based scRNA-seq and Illumina sequencing. We acknowledge the Single-Cell Genomics Core Facility and sequencing pipeline at the Wellcome Sanger Institute for plate-based Smart-seq2 and scATAC-seq processing. Data availability: All relevant data from this study, including raw flow-cytometry data, are available from the corresponding author upon request. Raw single-cell RNA sequencing data from our previous publication have been deposited in the ArrayExpress under accession number E-MTAB-4388. Raw scRNA-seq data, bulk ATAC-seq data and scATAC-seq data generated from the current manuscript have been deposited in the ArrayExpress under accession numbers E-MTAB-9317 (10x Genomics scRNAseq data), E-MTAB-9393 (bulk ATAC-seq data), E-MTAB-9403 (Smart-seq2 data), and E-MTAB-9402 (scATAC-seq data). JASPAR 2016 database (version 1.14.0) was used for transcription factor motif analyses. These authors contributed equally: Megan S. F. Soon, Hyun Jae Lee, Jessica A. Engel. These authors jointly supervised this work: Sarah A. Teichmann, Ashraful Haque. Author Contributions: A.H. conceived the study with T.L., K.R.J. and S.A.T. A.H. led efforts to acquire funding and managed the project in consultation with S.A.T. M.S.F.S., H.J.L. and J.A.E. ran the study equally, managing different aspects of cellular immunology, single-cell genomics and computational biology—first authorship order is determined by workload. B.S.T., C.P.S.P., L.S.C., P.L., R.N.H., X.C., K.R.J. and L.I.M.L. carried out experimentation in consultation with M.S.F.S., H.J.L., J.A.E., S.A.T. and A.H. G.T.B., C.R.E. and S.W.L. assisted in experimental design and data analysis and interpretation. M.S.F.S., H.J.L., J.A.E., J.S., C.G.W., M.L.M., M.B., L.T.K., S.W. and D.S.K. conducted analysis in consultation with A.H., S.A.T., V.S. and M.P.D. M.S.F.S., H.J.L., J.A.E. and J.S. interpreted results in consultation with A.H., S.A.T. and K.R.J. A.H., M.S.F.S., H.J.L. and J.A.E. wrote the manuscript. The authors declare no competing interests. Peer review information: Peer reviewer reports are available. Zoltan Fehervari was the primary editor on this article and managed its editorial process and peer review in collaboration with the rest of the editorial team.
Funding AgencyGrant Number
National Health and Medical Research Council1126399
European Research Council (ERC)ThDEFINE
Subject Keywords:Gene regulation in immune cells; Immunological memory; Malaria
Issue or Number:12
Record Number:CaltechAUTHORS:20190619-090153443
Persistent URL:
Official Citation:Soon, M.S.F., Lee, H.J., Engel, J.A. et al. Transcriptome dynamics of CD4+ T cells during malaria maps gradual transit from effector to memory. Nat Immunol 21, 1597–1610 (2020).
Usage Policy:No commercial reproduction, distribution, display or performance rights in this work are provided.
ID Code:96518
Deposited By: Tony Diaz
Deposited On:19 Jun 2019 17:08
Last Modified:25 Nov 2020 20:58

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