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

: Megan S. F. Soon, Hyun Jae Lee, Jessica A. Engel, Jasmin Straube, Bryce S. Thomas, Clara P. S. Pernold, Lachlan S. Clarke, Pawat Laohamonthonkul, Rohit N. Haldar, Cameron G. Williams, Lianne I. M. Lansink, Marcela L. Moreira, Michael Bramhall, Lambros T. Koufariotis, Scott Wood, Xi Chen, Kylie R. James, Tapio Lönnberg, Steven W. Lane, Gabrielle T. Belz, Christian R. Engwerda, David S. Khoury, Miles P. Davenport, Valentine Svensson, Sarah A. Teichmann, Ashraful Haque

Publisher: NATURE RESEARCH

: 2020

: Nature Immunology

: NATURE IMMUNOLOGY

: NAT IMMUNOL

: 21

: 12

: 1597

: 1610

: 36

: 1529-2908

: 1529-2916

DOI: https://doi.org/10.1038/s41590-020-0800-8

The dynamics of CD4(+) T cell memory development remain to be examined at genome scale. In malaria-endemic regions, anti-malarial 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(H)1) and follicular helper T (T-FH) transcriptomes contracted and partially coalesced over three weeks. Progeny of single clones populated T(H)1 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(H)1 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/).