Nideffer et al. (15) examined the malaria-specific CD4⁺ T cell response in a pediatric population infected with P. falciparum (Pf). (A) They identified the combination of CD127^lo and CXCR6⁺ as markers that captured a larger fraction of IL-10⁺ memory CD4⁺ T cells (defined as Tr1 cells) than conventional CD49b/LAG-3 or CCR5/PD-1. However, activated Tr1 cells downregulated CXCR6 and were missed by the CD127low/CXCR6⁺ combination, and approximately 10% of the cells inside the gate were Foxp3⁺ Tregs. The phenotype was validated by scRNA-seq, setting a new standard for Tr1 marker identification. (B) Tr1 cells expanded during symptomatic malaria and produced more IL-10 and IFN-γ upon infection. They were a major source of Pf-specific IL-10 and IFN-γ (not Th1 cells) and suppressed responder T cell proliferation in an IL-10–dependent manner. (C) A longitudinal study in a high-risk pediatric population found that Tr1 expansion and activation coincided with the onset of symptomatic malaria. Higher Tr1 frequencies were associated with reduced symptomatic malaria but also with prolonged infection, a potential trade-off between disease tolerance and parasite clearance whose causality remains unresolved.