A complete understanding of the mechanisms underlying the acquisition of protective immunity is crucial to improve vaccine strategies to eradicate malaria. However, it is still unclear whether recognition of damage signals influences the immune response to Plasmodium infection. Adenosine triphosphate (ATP) accumulates in infected erythrocytes and is released into the extracellular milieu through ion channels in the erythrocyte membrane or upon erythrocyte rupture. The P2X7 receptor senses extracellular ATP and induces CD4 T cell activation and death. Here we show that P2X7 receptor promotes T helper 1 (Th1) cell differentiation to the detriment of follicular T helper (Tfh) cells during blood-stage Plasmodium chabaudi malaria. The P2X7 receptor was activated in CD4 T cells following the rupture of infected erythrocytes and these cells became highly responsive to ATP during acute infection. Moreover, mice lacking the P2X7 receptor had increased susceptibility to infection, which correlated with impaired Th1 cell differentiation. Accordingly, IL-2 and IFNγ secretion, as well as T-bet expression, critically depended on P2X7 signaling in CD4 T cells. Additionally, P2X7 receptor controlled the splenic Tfh cell population in infected mice by promoting apoptotic-like cell death. Finally, the P2X7 receptor was required to generate a balanced Th1/Tfh cell population with an improved ability to transfer parasite protection to CD4-deficient mice. This study provides a new insight into malaria immunology by showing the importance of P2X7 receptor in controlling the fine-tuning between Th1 and Tfh cell differentiation during P. chabaudi infection and thus in disease outcome.

全面了解获得保护性免疫的基本机制对于改善根除疟疾的疫苗策略至关重要。但是，尚不清楚损伤信号的识别是否影响对疟原虫感染的免疫反应。三磷酸腺苷（ATP）积累在受感染的红细胞中，并通过红细胞膜中的离子通道或在红细胞破裂时释放到细胞外环境中。P2X7受体感应细胞外ATP，并诱导CD4 T细胞活化和死亡。在这里，我们显示P2X7受体在血液阶段Chabaudi恶性疟原虫中促进T辅助1（Th1）细胞分化，从而损害滤泡T辅助（Tfh）细胞。疟疾。在感染的红细胞破裂后，CD4 T细胞中的P2X7受体被激活，这些细胞在急性感染过程中对ATP的反应变得高度敏感。此外，缺乏P2X7受体的小鼠对感染的敏感性增加，这与Th1细胞分化受损有关。因此，IL-2和IFNγ的分泌以及T-bet的表达主要取决于CD4 T细胞中的P2X7信号传导。此外，P2X7受体通过促进凋亡样细胞死亡来控制感染小鼠的脾Tfh细胞数量。最后，需要P2X7受体来产生平衡的Th1 / Tfh细胞群，并具有将寄生虫保护转移至CD4缺陷型小鼠的改善的能力。P。chabaudi感染，从而导致疾病结果。