Kurup Samarchith P, Obeng-Adjei Nyamekye, Anthony Scott M, Traore Boubacar, Doumbo Ogobara K, Butler Noah S, Crompton Peter D, Harty John T
Department of Microbiology and Immunology, University of Iowa Carver College of Medicine, Iowa City, Iowa, USA.
Laboratory of Immunogenetics, National Institute of Allergy and Infectious Diseases, US National Institutes of Health, Rockville, Maryland, USA.
Nat Med. 2017 Oct;23(10):1220-1225. doi: 10.1038/nm.4395. Epub 2017 Sep 11.
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) cells form a part of these responses, their influence remains disputed and their mode of action is unknown. Here we show that T cells expand in both humans and mice in blood-stage malaria and interfere with conventional T helper cell responses and follicular T helper (T)-B cell interactions in germinal centers. Mechanistically, T cells function in a critical temporal window to impede protective immunity through cytotoxic-T-lymphocyte-associated protein-4 (CTLA-4). Targeting T 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 cells and CTLA-4 in limiting antimalarial immunity.
疟疾由原生动物疟原虫引起，是一种极具破坏力的蚊媒疾病，有可能影响全球近一半人口。尽管人体产生了大量的T细胞和B细胞反应，但仍无法有效控制血液阶段的疟疾，也无法对再次感染产生无菌免疫。虽然叉头框P3（FOXP3）CD4调节性T（Treg）细胞是这些反应的一部分，但其影响仍存在争议，作用方式也尚不清楚。在这里，我们表明Treg细胞在人类和小鼠的血液阶段疟疾中均会扩增，并干扰生发中心的传统辅助性T细胞反应以及滤泡辅助性T（TFH）细胞与B细胞的相互作用。从机制上讲，Treg细胞在关键的时间窗口发挥作用，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。在此精确窗口靶向Treg细胞或CTLA-4可加速寄生虫清除，并在小鼠中产生针对血液阶段疟疾的跨物种免疫。我们的研究揭示了与血液阶段疟疾相关的免疫抑制关键机制，该机制会延迟寄生虫清除，并阻止对再次感染产生有效的适应性免疫。这些数据还揭示了Treg细胞和CTLA-4在限制抗疟疾免疫方面在时间上离散且可能在治疗上具有可行性的功能作用。
