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. Overall design: scRNA-seq and CITE-Seq analysis were performed on splenic Plasmodium-specific TCR transgenic CD4+ T cells from Plasmodium chabaudi chabaudi (Pcc)-infected C57BL/6 mice that were treated with either anti-IL-27 mAb or IgG control. Single cell data from IgG- and anti-IL-27 mAb-treated mice were collected and analyzed for days 7 and 28 post-infection (pi) time point, as well as day 14 pi timepoint from anti-IL-27 mAb-treated mouse, with 1 replicate each (total of 5 samples). CITE-Seq analysis made use of IgG2a control, CD49d, CD127 and KLRG1 as target markers.