School of Tropical Medicine and Global Health, Nagasaki University, Nagasaki, Japan.
Department of Infection Biology, Faculty of Infectious and Tropical Diseases, London School of Hygiene and Tropical Medicine, London, UK.
EMBO Mol Med. 2023 Dec 7;15(12):e17713. doi: 10.15252/emmm.202317713. Epub 2023 Oct 19.
Malaria infection elicits both protective and pathogenic immune responses, and IL-27 is a critical cytokine that regulate effector responses during infection. Here, we identified a critical window of CD4 T cell responses that is targeted by IL-27. Neutralization of IL-27 during acute infection with Plasmodium chabaudi expanded specific CD4 T cells, which were maintained at high levels thereafter. In the chronic phase, Plasmodium-specific CD4 T cells in IL-27-neutralized mice consisted mainly of CD127 KLRG1 and CD127 KLRG1 subpopulations that displayed distinct cytokine production, proliferative capacity, and are maintained in a manner independent of active infection. Single-cell RNA-seq analysis revealed that these CD4 T cell subsets formed independent clusters that express unique Th1-type genes. These IL-27-neutralized mice exhibited enhanced cellular and humoral immune responses and protection. These findings demonstrate that IL-27, which is produced during the acute phase of malaria infection, inhibits the development of unique Th1 memory precursor CD4 T cells, suggesting potential implications for the development of vaccines and other strategic interventions.
疟原虫感染会引发保护性和致病性免疫反应，IL-27 是一种关键的细胞因子，可调节感染期间的效应器反应。在这里，我们确定了 CD4 T 细胞反应的一个关键窗口期，该窗口期是由 IL-27 靶向的。在感染疟原虫 chabaudi 的急性阶段，中和 IL-27 会扩增特定的 CD4 T 细胞，此后这些细胞会保持高水平。在慢性阶段，IL-27 中和小鼠中的疟原虫特异性 CD4 T 细胞主要由 CD127 KLRG1 和 CD127 KLRG1 亚群组成，这些亚群表现出不同的细胞因子产生、增殖能力，并以独立于活性感染的方式维持。单细胞 RNA-seq 分析显示，这些 CD4 T 细胞亚群形成了独立的簇，表达独特的 Th1 型基因。这些接受 IL-27 中和的小鼠表现出增强的细胞和体液免疫反应和保护作用。这些发现表明，IL-27 在疟疾感染的急性期产生，会抑制独特的 Th1 记忆前体 CD4 T 细胞的发育，这表明其对疫苗和其他战略干预措施的发展具有潜在影响。
