We examined transcriptional changes in CD4⁺ T cells during blood-stage Plasmodium falciparum infection in individuals without a history of previous parasite exposure. Transcription of CXCL8 (encoding interleukin 8) in CD4⁺ T cells was identified as an early biomarker of submicroscopic P. falciparum infection, with predictive power for parasite growth. Following antiparasitic drug treatment, a CD4⁺ T-cell regulatory phenotype developed. PD1 expression on CD49b⁺CD4⁺ T (putative type I regulatory T) cells after drug treatment negatively correlated with earlier parasite growth. Blockade of PD1 but no other immune checkpoint molecules tested increased interferon γ and interleukin 10 production in an ex vivo antigen-specific cellular assay at the peak of infection. These results demonstrate the early development of an immunoregulatory CD4⁺ T-cell phenotype in blood-stage P. falciparum infection and show that a selective immune checkpoint blockade may be used to modulate early developing antiparasitic immunoregulatory pathways as part of malaria vaccine and/or drug treatment protocols.