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/).

CD4 ⁺ T细胞记忆发展的动力学仍有待在基因组规模上进行检查。在疟疾流行地区，抗疟疾化学预防在停止后能长期提供保护，并与对CD4 ⁺ T细胞的影响有关。我们应用单细胞RNA测序和计算模型来追踪疟原虫感染和治疗过程中的记忆发育。在没有中央记忆先兆的情况下，在三个星期内，两条轨迹发展为T辅助1（T _H 1）和滤泡辅助T（T _FH）转录组，并部分合并。单个克隆的后代遍布T _H 1和T _FH轨迹和命运图表明，血统可塑性极小。揭示了T _FH和中枢记忆之间的关系，抗疟药调节了这些反应并增强了T _H 1的回忆。最后，单细胞表观基因组学证实效应器之间的异质性在记忆中被部分重置。因此，在疟疾期间，CD4 ⁺ T细胞中的效应子到记忆的过渡是逐渐的，并由抗寄生虫药物调节。提供了图形用户界面，用于检查基因表达动态和基因与基因的相关性（http://haquelab.mdhs.unimelb.edu.au/cd4_memory/）。