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Published December 2020 | Submitted + Supplemental Material
Journal Article Open

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

Abstract

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 (http://haquelab.mdhs.unimelb.edu.au/cd4_memory/).

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.

Attached Files

Submitted - 675967.full.pdf

Supplemental Material - 41590_2020_800_Fig10_ESM.webp

Supplemental Material - 41590_2020_800_Fig11_ESM.webp

Supplemental Material - 41590_2020_800_Fig12_ESM.webp

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Supplemental Material - 41590_2020_800_Fig17_ESM.webp

Supplemental Material - 41590_2020_800_Fig8_ESM.webp

Supplemental Material - 41590_2020_800_Fig9_ESM.webp

Supplemental Material - 41590_2020_800_MOESM1_ESM.pdf

Supplemental Material - 41590_2020_800_MOESM2_ESM.pdf

Supplemental Material - 41590_2020_800_MOESM3_ESM.pdf

Supplemental Material - 41590_2020_800_MOESM4_ESM.xlsx

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Additional details

Created:
August 22, 2023
Modified:
October 23, 2023