Key Points γδ T cells expand and develop cytolytic potential in response to malaria cultures. γδ T cells inhibit parasite growth in a contact- and granzyme-dependent manner. Granulysin delivers granzyme B into RBCs to kill late-stage parasites. Plasmodium spp., the causative agent of malaria, have a complex life cycle. The exponential growth of the parasites during the blood stage is responsible for almost all malaria-associated morbidity and mortality. Therefore, tight immune control of the intraerythrocytic replication of the parasite is essential to prevent clinical malaria. Despite evidence that the particular lymphocyte subset of γδ T cells contributes to protective immunity during the blood stage in naive hosts, their precise inhibitory mechanisms remain unclear. Using human PBMCs, we confirmed in this study that γδ T cells specifically and massively expanded upon activation with Plasmodium falciparum culture supernatant. We also demonstrate that these activated cells gain cytolytic potential by upregulating cytotoxic effector proteins and IFN-γ. The killer cells bound to infected RBCs and killed intracellular P. falciparum via the transfer of the granzymes, which was mediated by granulysin in a stage-specific manner. Several vital plasmodial proteins were efficiently destroyed by granzyme B, suggesting proteolytic degradation of these proteins as essential in the lymphocyte-mediated death pathway. Overall, these data establish a granzyme- and granulysin-mediated innate immune mechanism exerted by γδ T cells to kill late-stage blood-residing P. falciparum.

中文翻译：

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γδ T 细胞在血液晚期以依赖颗粒酶和颗粒溶素的机制杀死恶性疟原虫

关键点 γδ T 细胞扩增并产生对疟疾培养物的细胞溶解潜力。γδ T 细胞以接触和颗粒酶依赖性方式抑制寄生虫生长。Granulysin 将颗粒酶 B 输送到红细胞中以杀死晚期寄生虫。疟原虫属是疟疾的病原体，具有复杂的生命周期。血液阶段寄生虫的指数增长是几乎所有与疟疾相关的发病率和死亡率的原因。因此，对寄生虫红细胞内复制的严格免疫控制对于预防临床疟疾至关重要。尽管有证据表明 γδ T 细胞的特定淋巴细胞亚群在幼稚宿主的血液阶段有助于保护性免疫，但它们的确切抑制机制仍不清楚。使用人类 PBMC，我们在本研究中证实，γδ T 细胞在用恶性疟原虫培养物上清液激活后特异性地大量扩增。我们还证明这些活化的细胞通过上调细胞毒性效应蛋白和 IFN-γ 获得细胞溶解潜力。杀伤细胞与受感染的红细胞结合并通过颗粒酶的转移杀死细胞内恶性疟原虫，这是由颗粒溶素以特定阶段的方式介导的。颗粒酶 B 有效破坏了几种重要的疟原虫蛋白质，表明这些蛋白质的蛋白水解降解是淋巴细胞介导的死亡途径中必不可少的。总体而言，这些数据建立了由 γδ T 细胞发挥的颗粒酶和颗粒溶素介导的先天免疫机制，以杀死晚期血液中的恶性疟原虫。