QIMR Berghofer Medical Research Institute, Brisbane, Australia.
Griffith University, School of Environment and Science, Nathan, Australia.
J Clin Invest. 2023 Oct 2;133(19):e169417. doi: 10.1172/JCI169417.
The development of highly effective malaria vaccines and improvement of drug-treatment protocols to boost antiparasitic immunity are critical for malaria elimination. However, the rapid establishment of parasite-specific immune regulatory networks following exposure to malaria parasites hampers these efforts. Here, we identified stimulator of interferon genes (STING) as a critical mediator of type I interferon production by CD4+ T cells during blood-stage Plasmodium falciparum infection. The activation of STING in CD4+ T cells by cyclic guanosine monophosphate-adenosine monophosphate (cGAMP) stimulated IFNB gene transcription, which promoted development of IL-10- and IFN-γ-coproducing CD4+ T (type I regulatory [Tr1]) cells. The critical role for type I IFN signaling for Tr1 cell development was confirmed in vivo using a preclinical malaria model. CD4+ T cell sensitivity to STING phosphorylation was increased in healthy volunteers following P. falciparum infection, particularly in Tr1 cells. These findings identified STING expressed by CD4+ T cells as an important mediator of type I IFN production and Tr1 cell development and activation during malaria.
开发高效的疟疾疫苗和改进药物治疗方案以增强抗寄生虫免疫，对于消除疟疾至关重要。然而，疟疾寄生虫暴露后寄生虫特异性免疫调节网络的迅速建立阻碍了这些努力。在这里，我们发现刺激干扰素基因（STING）是 CD4+T 细胞在疟原虫感染的血期产生 I 型干扰素的关键介质。cGAMP 激活 CD4+T 细胞中的 STING 刺激 IFNB 基因转录，促进产生 IL-10 和 IFN-γ的 CD4+T（I 型调节性[Treg]）细胞的发展。在疟疾的临床前模型中，体内实验证实了 I 型 IFN 信号对 Treg 细胞发育的关键作用。疟原虫感染后，健康志愿者的 CD4+T 细胞对 STING 磷酸化的敏感性增加，尤其是在 Treg 细胞中。这些发现确定了 CD4+T 细胞表达的 STING 是疟疾期间 I 型 IFN 产生和 Treg 细胞发育和激活的重要介质。
