Department of Infectious Diseases, Guangdong Provincial Key Laboratory of Major Obstetric Diseases, The Third Affiliated Hospital of Guangzhou Medical University, Guangzhou, China.
Department of Basic Medical Science, China Sino-French Hoffmann Institute, Guangzhou Medical University, Guangzhou, China.
Front Immunol. 2022 Aug 24;13:942862. doi: 10.3389/fimmu.2022.942862. eCollection 2022.
The morbidity and mortality of malaria are still high. Programmed cell death-1(PD-1) is an important co-inhibitory factor and CD8 T cells with PD-1 were reported to be exhausted cells. It remains unknown what the role of CD4 T cells expressing PD-1 is and what the upstream regulating molecules of PD-1 in CD4 T cells are. The C57BL/6 mice were injected with () in this study. Expressions of PD-1, activation markers, and cytokines were tested. The differentially expressed genes between PD-1 CD4 T cells were detected by microarray sequencing. Western blot, chromatin immunoprecipitation (ChIP), siRNA, hypoxia inducible factor-1α (HIF-1α) inducer and inhibitor were used to explore PD-1's upstream molecules, respectively. The proportions of PD-1 CD4 T cells increased post infection. PD-1 CD4 T cells expressed more activated surface markers and could produce more cytokines. Nuclear factor of activated T cells 1 (NFATc1) was found to be a key transcription factor to induce PD-1 expression after infection. Both the inducer and the inhibitor of HIF-1α could change the expressions of NFATc1 and PD-1 and , respectively. Taken together, infection induced NFATc1 expression by HIF-1α. The highly expressed NFATc1 entered the nucleus and initiated PD-1 expression. PD-1 CD4 T cells appeared to be more activated and could secrete more cytokines to regulate the host's immune responses against malaria.
疟疾的发病率和死亡率仍然很高。程序性细胞死亡蛋白 1（PD-1）是一种重要的共抑制因子，已有报道称表达 PD-1 的 CD8 T 细胞是耗竭细胞。目前尚不清楚表达 PD-1 的 CD4 T 细胞的作用是什么，以及 CD4 T 细胞中 PD-1 的上游调节分子是什么。在本研究中，用 （） 注射 C57BL/6 小鼠。检测 PD-1、激活标志物和细胞因子的表达。通过微阵列测序检测 PD-1 CD4 T 细胞之间差异表达的基因。分别使用 Western blot、染色质免疫沉淀（ChIP）、siRNA、缺氧诱导因子-1α（HIF-1α）诱导剂和抑制剂来探讨 PD-1 的上游分子。感染后 PD-1 CD4 T 细胞的比例增加。PD-1 CD4 T 细胞表达更多的激活表面标志物，并能产生更多的细胞因子。在感染后，发现激活 T 细胞核因子 1（NFATc1）是诱导 PD-1 表达的关键转录因子。HIF-1α 的诱导剂和抑制剂都可以改变 NFATc1 和 PD-1 的表达，分别是 和 。综上所述，感染通过 HIF-1α 诱导 NFATc1 表达。高表达的 NFATc1 进入细胞核并启动 PD-1 表达。PD-1 CD4 T 细胞似乎更活跃，并能分泌更多细胞因子来调节宿主对疟疾的免疫反应。
