In this issue, Nideffer et al. (15) define the functional role of human Tr1 cells during pediatric Plasmodium falciparum (Pf) infection. By integrating phenotypic enrichment with single-cell transcriptomic datasets, the authors demonstrated that Tr1 cells were a major component of the malaria-specific CD4+ T cell response in this pediatric cohort (Figure 1A), adding to growing evidence that Tr1 cells and regulatory programs are a core feature of antiparasitic immunity (7, 13, 16–18).

Tr1 cells in human malaria: identification, function, and clinical trade off. 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 CD127lo 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.

Beyond abundance and expansion, Tr1 cells identified by Nideffer et al. contributed substantially to the antigen-specific response. They represented a prominent source of IL-10 following stimulation with Plasmodium-infected red blood cells and contributed considerably to IFN-γ production in an antigen-specific context (Figure 1B). Conventionally defined Th1 cells from the same patients produced little IFN-γ upon Pf-specific restimulation, suggesting that Tr1 cells, rather than classical Th1 cells, are the major source of malaria-specific IFN-γ in this setting. While IFN-γ and IL-10 coproduction has been observed in malaria-specific CD4+ T cell responses (7, 16, 19), Nideffer et al. directly linked this bifunctionality to a phenotypically defined Tr1 population adopting hybrid regulatory-effector states.

Furthermore, Tr1 cells also appeared linked to systemic immune regulation. Their frequency correlated with circulating IL-10, IFN-γ, granzyme A, and LAG-3, indicating participation in shaping the inflammatory environment during infection. Longitudinal analyses further showed Tr1 cell expansion during symptomatic malaria and associations with disease trajectory, consistent with a role for Tr1 cells in modulating clinical outcomes. However, whether Tr1 cells actively enforce disease tolerance or instead expand because of high antigen burden remains unresolved. Further investigation will be needed to establish if a causal relationship between Tr1 cells and reduced symptoms during malaria infection exists.

Importantly, higher Tr1 frequencies were associated with reduced symptomatic malaria, consistent with their established role in limiting immunopathology and promoting resolution of inflammation (20, 21), but also with prolonged infection, suggesting a trade-off between disease tolerance and parasite clearance (Figure 1C). In endemic regions, repeated Pf exposure often leads to asymptomatic infections, implying active immune regulation (22, 23). Nideffer et al. provide a potential explanation: pediatric patients with higher Tr1 frequencies had lower probability of developing symptomatic malaria. Beyond malaria, Tr1 cells have been implicated in other infectious diseases (7, 20, 21, 24), raising the question of whether the protective-but-persistent trade off observed here generalizes to other contexts.