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

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 _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/ ).