Long-lived CD4+IFN-γ+ T cells rather than short-lived CD4⁺IFN-γ⁺IL-10⁺ T cells initiate rapid IL-10 production to suppress anamnestic T cell responses during secondary malaria infection

CD4⁺ T cells that produce IFN-γ are the source of host-protective IL-10 during primary infection with a number of different pathogens, including Plasmodium spp. The fate of these CD4⁺IFN-γ⁺IL-10⁺ T cells following clearance of primary infection and their subsequent influence on the course of repeated infections is, however, presently unknown. In this study, utilizing IFN-γ–yellow fluorescent protein (YFP) and IL-10–GFP dual reporter mice, we show that primary malaria infection–induced CD4⁺YFP⁺GFP⁺ T cells have limited memory potential, do not stably express IL-10, and are disproportionately lost from the Ag-experienced CD4⁺ T cell memory population during the maintenance phase postinfection. CD4⁺YFP⁺GFP⁺ T cells generally exhibited a short-lived effector rather than effector memory T cell phenotype postinfection and expressed high levels of PD-1, Lag-3, and TIGIT, indicative of cellular exhaustion. Consistently, the surviving CD4⁺YFP⁺GFP⁺ T cell–derived cells were unresponsive and failed to proliferate during the early phase of secondary infection. In contrast, CD4⁺YFP⁺GFP− T cell–derived cells expanded rapidly and upregulated IL-10 expression during secondary infection. Correspondingly, CD4⁺ T cells were the major producers within an accelerated and amplified IL-10 response during the early stage of secondary malaria infection. Notably, IL-10 exerted quantitatively stronger regulatory effects on innate and CD4⁺ T cell responses during primary and secondary infections, respectively. The results in this study significantly improve our understanding of the durability of IL-10–producing CD4⁺ T cells postinfection and provide information on how IL-10 may contribute to optimized parasite control and prevention of immune-mediated pathology during repeated malaria infections.