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.

中文翻译：

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调节性T细胞可通过CTLA-4阻止对血液阶段疟疾的急性和长期免疫。

由原生动物疟原虫引起的疟疾是毁灭性的蚊媒传播疾病，有可能影响全球近一半的人口。尽管出现大量的T细胞和B细胞反应，人类仍无法有效控制血液阶段的疟疾或发展对再感染的杀菌免疫力。尽管叉头盒P3（FOXP3）⁺ CD4 ⁺调节性T（T _reg）细胞构成了这些反应的一部分，但它们的影响仍然存在争议，其作用方式尚不清楚。在这里，我们显示T _reg细胞在人和小鼠的血液阶段疟疾中均会扩增，并在生发中心干扰常规T辅助细胞反应和滤泡T辅助细胞（T _FH）-B细胞相互作用。机械上，T _reg细胞在关键的时间窗内发挥功能，从而通过细胞毒性T淋巴细胞相关蛋白4（CTLA-4）阻碍保护性免疫。在这个精确的窗口中靶向T _reg细胞或CTLA-4可以加速寄生虫清除并在小鼠中产生对血期疟疾的超越物种的免疫力。我们的研究揭示了与血液阶段疟疾相关的免疫抑制的关键机制，该机制可延迟寄生虫清除并阻止针对再感染的有效适应性免疫的发展。这些数据还揭示了T _reg细胞和CTLA-4在限制抗疟疾免疫力方面在时间上是离散的，并且可能在治疗上具有令人满意的功能性作用。