Regulatory T cells impede acute and long-term immunity to blood-stage malaria through CTLA-4

Malaria, caused by the protozoan Plasmodium, is a devastating mosquito-borne disease with the potential to affect nearly half the world's population. Despite mounting substantial T and B cell responses, humans fail to efficiently control blood-stage malaria or develop sterilizing immunity to reinfections. Although forkhead box P3 (FOXP3)⁺CD4⁺ regulatory T (T_reg) cells form a part of these responses, their influence remains disputed and their mode of action is unknown. Here we show that T_reg cells expand in both humans and mice in blood-stage malaria and interfere with conventional T helper cell responses and follicular T helper (T_FH)-B cell interactions in germinal centers. Mechanistically, T_reg cells function in a critical temporal window to impede protective immunity through cytotoxic-T-lymphocyte-associated protein-4 (CTLA-4). Targeting T_reg cells or CTLA-4 in this precise window accelerated parasite clearance and generated species-transcending immunity to blood-stage malaria in mice. Our study uncovers a critical mechanism of immunosuppression associated with blood-stage malaria that delays parasite clearance and prevents development of potent adaptive immunity to reinfection. These data also reveal a temporally discrete and potentially therapeutically amenable functional role for T_reg cells and CTLA-4 in limiting antimalarial immunity.