IL-27 produced during acute malaria infection regulates Plasmodium-specific memory CD4⁺ T cells

Malaria infection elicits both protective and pathogenic immune responses, and IL-27 is a critical cytokine that regulate effector responses during infection. Here, we identified a critical window of CD4⁺ T cell responses that is targeted by IL-27. Neutralization of IL-27 during acute infection with Plasmodium chabaudi expanded specific CD4⁺ T cells, which were maintained at high levels thereafter. In the chronic phase, Plasmodium-specific CD4⁺ T cells in IL-27-neutralized mice consisted mainly of CD127⁺ KLRG1^- and CD127^- KLRG1⁺ subpopulations that displayed distinct cytokine production, proliferative capacity, and are maintained in a manner independent of active infection. Single-cell RNA-seq analysis revealed that these CD4⁺ T cell subsets formed independent clusters that express unique Th1-type genes. These IL-27-neutralized mice exhibited enhanced cellular and humoral immune responses and protection. These findings demonstrate that IL-27, which is produced during the acute phase of malaria infection, inhibits the development of unique Th1 memory precursor CD4⁺ T cells, suggesting potential implications for the development of vaccines and other strategic interventions.